Autoregulatory Loop Research Articles

Retraction Notice to: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development.

Retraction Notice to: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development.

Suppressive Role of ACVR1/ALK2 in Basal and TGFβ1-Induced Cell Migration in Pancreatic Ductal Adenocarcinoma Cells and Identification of a Self-Perpetuating Autoregulatory Loop Involving the Small GTPase RAC1b.

Pancreatic ductal adenocarcinoma (PDAC) cells are known for their high invasive/metastatic potential, which is regulated in part by the transforming growth factor β1 (TGFβ1). The involvement of at least two type I receptors, ALK5 and ALK2, that transmit downstream signals of the TGFβ via different Smad proteins, SMAD2/3 and SMAD1/5, respectively, poses the issue of their relative contribution in regulating cell motility. Real-time cell migration assays revealed that the selective inhibition of ALK2 by RNAi or dominant-negative interference with a kinase-dead mutant (ALK2-K233R) strongly enhanced the cells’ migratory activity in the absence or presence of TGFβ1 stimulation. Ectopic ALK2-K233R expression was associated with an increase in the protein levels of RAC1 and its alternatively spliced isoform, RAC1b, both of which are implicated in driving cell migration and invasion. Conversely, the RNAi-mediated knockdown or CRISPR/Cas9-mediated knockout of RAC1b resulted in the upregulation of the expression of ALK2, but not that of the related BMP type I receptors, ALK3 or ALK6, and elevated the phosphorylation of SMAD1/5. PDAC is a heterogeneous disease encompassing tumors with different histomorphological subtypes, ranging from epithelial/classical to extremely mesenchymal. Upon treatment of various established and primary PDAC cell lines representing these subtypes with the ALK2 inhibitor, LDN-193189, well-differentiated, epithelial cell lines responded with a much stronger increase in the basal and TGFβ1-dependent migratory activity than poorly differentiated, mesenchymal ones. These data show that (i) ALK2 inhibits migration by suppressing RAC1/RAC1b proteins, (ii) ALK2 and RAC1b act together in a self-perpetuating the autoregulatory negative feedback loop to mutually control their expression, and (iii) the ALK2 antimigratory function appears to be particularly crucial in protecting epithelial subtype cells from becoming invasive, both spontaneously and in a TGFβ-rich tumor microenvironment.

Elucidating the immunohistochemistry of Nanog: A transcription marker in the oral squamous cell carcinoma with emphasis on its origin as embryonic stem cell.

Nanog is a key transcription factor regulating pluripotency in mammalian early embryos and pluripotent stem cells. Nanog plays a central role in pluripotency and forms autoregulatory loops to maintain ESC (embryonic stem cell) identity. Oral squamous cell carcinoma (OSCC) is an extensively studied malignancy that occurs due to accumulated genetic and epigenetic changes. Hence, the current study was done to evaluate role of Nanog in OSCC. The present study was done to evaluate Nanog role in OSCC. Thirty normal subjects and 30 patients of oral squamous cell carcinoma (OSCC) were included in study. The cases were staged clinically based on tumour node metastasis (TNM) staging and graded histopathologically using modified Broder's grading system. Thirty tissue sections of OSCC were subjected to immunohistochemistry (IHC) with Nanog antibody. Random fields were chosen and 300 cells were counted in five areas and mean percentage of immunopositive cells were calculated. The results were analysed using ANOVA test. The results demonstrated a statistically significant difference between normal subjects and in patients with OSCC with respect to mean of IHC score (P = 0.0001*). High mean values for Nanog in tissue with OSCC in both histopathological (P = 0.0001*) and clinical grading (P = 0.0276*) with statistically significant result were observed. The increased expression of Nanog in patients with OSCC was statistically significant, suggesting its role as diagnostic biomarker. Statistically significant result with respect to clinical staging and histopathological grading of Nanog expression in patients with OSCC suggests its role as prognostic biomarker also.

A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours.

Single-strand selective uracil–DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes relevant for cancer development and treatment response. Based on this, we hypothesized that the dominating function of SMUG1 in cancer might be ascribed to functions other than BER. We define a bad prognosis signature for SMUG1 by mapping out the SMUG1 interaction network and found that high expression of genes in the bad prognosis network correlated with lower survival probability in ER+ breast cancer. Interestingly, we identified hsa-let-7b-5p microRNA as an upstream regulator of the SMUG1 interactome. Expression of SMUG1 and hsa-let-7b-5p were negatively correlated in breast cancer and we found an inhibitory auto-regulatory loop between SMUG1 and hsa-let-7b-5p in the MCF7 breast cancer cells. We conclude that SMUG1 functions in a gene regulatory network that influence the survival and treatment response in several cancers.

Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia

SummaryTranscriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed transcription factor (TF) vulnerabilities in leukemia and uncovered TF clusters that exhibit context-specific vulnerabilities within and between different subtypes of leukemia. Among these TF clusters, we demonstrated that acute myeloid leukemia (AML) with high IRF8 expression was addicted to MEF2D. MEF2D and IRF8 form an autoregulatory loop via direct binding to mutual enhancer elements. One important function of this circuit in AML is to sustain PU.1/MEIS1 co-regulated transcriptional outputs via stabilizing PU.1’s chromatin occupancy. We illustrated that AML could acquire dependency on this circuit through various oncogenic mechanisms that results in the activation of their enhancers. In addition to forming a circuit, MEF2D and IRF8 can also separately regulate gene expression, and dual perturbation of these two TFs leads to a more robust inhibition of AML proliferation. Collectively, our results revealed a TF circuit essential for AML survival.

Circadian Regulation of Hormonal Timing and the Pathophysiology of Circadian Dysregulation.

Circadian rhythms are endogenously generated, daily patterns of behavior and physiology that are essential for optimal health and disease prevention. Disruptions to circadian timing are associated with a host of maladies, including metabolic disease and obesity, diabetes, heart disease, cancer, and mental health disturbances. The circadian timing system is hierarchically organized, with a master circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks throughout the CNS and periphery. The SCN receives light information via a direct retinal pathway, synchronizing the master clock to environmental time. At the cellular level, circadian rhythms are ubiquitous, with rhythms generated by interlocking, autoregulatory transcription-translation feedback loops. At the level of the SCN, tight cellular coupling maintains rhythms even in the absence of environmental input. The SCN, in turn, communicates timing information via the autonomic nervous system and hormonal signaling. This signaling couples individual cellular oscillators at the tissue level in extra-SCN brain loci and the periphery and synchronizes subordinate clocks to external time. In the modern world, circadian disruption is widespread due to limited exposure to sunlight during the day, exposure to artificial light at night, and widespread use of light-emitting electronic devices, likely contributing to an increase in the prevalence, and the progression, of a host of disease states. The present overview focuses on the circadian control of endocrine secretions, the significance of rhythms within key endocrine axes for typical, homeostatic functioning, and implications for health and disease when dysregulated. © 2022 American Physiological Society. Compr Physiol 12: 1-30, 2022.

Patterns and Crucial Regulation of Alternative Splicing During Early Development in Zebrafish

Many vertebrate genes generate multiple transcript variants that may encode functionally distinct protein isoforms, but the transcriptomes of various developmental stages are poorly defined. Identifying the transcriptome and its regulation during the normal developmental process is the key to deciphering the developmental stage-specific functions of genes. Here we presented a systematic assessment of the temporal alternative splicing (AS) events during the critical development stages to capture the dynamic gene expression changes and AS in zebrafish. An unexpected transcriptome complexity generated by AS was observed during zebrafish development. The patterns of AS events varied substantially among developmental stages despite the similarities in the total proportion of AS genes. We further found that AS afforded substantial functional diversification of genes through the generation of stage-specific AS events from broadly protein-coding genes as an essential developmental regulatory mechanism. Skipped exon (SE) showed the strongest signals among developmental AS (devAS), suggesting that devAS events generated by SE may be necessary for the normal development of zebrafish. Most developmental genes regulated by AS mechanisms were not modulated in terms of their overall expression levels, indicating that AS shaped the transcriptome independently from transcriptional regulation during development. 128-cell stage was a critical stage for gene transcription during embryonic development. Splicing factors as an essential developmental regulator underwent AS in the potential autoregulatory feedback loop and expressed multiple isoforms. Thus, zebrafish development was shaped by an interplay of programs controlling gene expression levels and AS. Overall, we provided a global view of developmental patterns of AS during zebrafish development and revealed that AS transitions were the crucial regulatory component of zebrafish embryonic development.

Role of macrophages in prevention and control of diseases and their upregulation through cowpathy

Mammalian macrophages are present from mid gestation onwards, helping to maintain physiologic homeostasis. During embryonic development in the mouse, macrophages emerge from yolk sac and foetal liver progenitors and survive as diverse, self-renewing tissue-resident populations in many organs. After birth, bone marrow-derived blood monocytes are recruited to replenish tissue resident populations and to meet additional demands during inflammation, infection, and metabolic changes. Signals that generate and maintain inflammation, as well as signals that shut down the process, are normally controlled carefully in the inflammatory process. Inflammation goes uncontrolled when the two signals are out of sync, causing cellular and tissue damage. Macrophages are a key component of the mononuclear phagocyte system, which includes blood monocytes and tissue macrophages. Monocytes travel from the bloodstream into various organs and convert into macrophages. Antigen presentation, phagocytosis, and immunomodulation through the production of different cytokines and growth factors are three key functions of macrophages in inflammation. Macrophages are critical in the onset, maintenance, and resolution of inflammation. During the inflammatory process, they are activated and deactivated. Cytokines (interferon, granulocyte-monocyte colony stimulating factor, and tumour necrosis factor), bacterial lipopolysaccharide, extracellular matrix proteins, and other chemical mediators are all examples of activation signals. The elimination or deactivation of mediators and inflammatory effector cells inhibits inflammation, allowing the host to heal damaged tissues. Anti-inflammatory cytokines (interleukin 10 and transforming growth factor ß) and cytokine antagonists, which are primarily generated by macrophages, deactivate active macrophages. Macrophages are involved in the inflammatory process' autoregulatory loop. We outline macrophage activities in inflammation and healing in response to

Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The retinoblastoma protein (RB1), a regulator of cell proliferation, is functionally inactivated in HCC by CYCLIN D/E-mediated phosphorylation. However, the mechanism of RB1-inactivation is unclear because only small percentages of HCCs exhibit amplification of CYCLIN D/E or mutations in the CDK-inhibitory genes. We show that FOXM1, which is overexpressed and critical for HCC, plays essential roles in inactivating RB1 and suppressing RB1-induced senescence of the HCC cells. Mechanistically, FOXM1 binds RB1 and DNMT3B to repress the expression of FOXO1, leading to a decrease in the levels of the CDK-inhibitors, creating an environment for phosphorylation and inactivation of RB1. Consistent with that, inhibition of FOXM1 causes increased expression of FOXO1 with consequent activation of RB1, leading to senescence of the HCC cells, in vitro and in vivo. Also, repression-deficient mutants of FOXM1 induce senescence that is blocked by depletion of RB1 or FOXO1. We provide evidence that human HCCs rely upon this FOXM1-FOXO1 axis for phosphorylation and inactivation of RB1. The observations demonstrate the existence of a new autoregulatory loop of RB1-inactivation in HCC involving a FOXM1-FOXO1 axis that is required for phosphorylation of RB1 and for aggressive progression of HCC.

Review on circadian rhythm the role of core clock gene expression during sleep in epileptic syndrome

Circadian rhythm is a 24 hour or a day’s rhythmic oscillations with physiological and behavioural changes that is internally governed by the brain. This activity is generally anticipated by the internal and external cues from the environment. In circadian rhythm of our body is regulated by a transcriptional –translational Auto-regulatory loop which leads to the molecular oscillations of our “core clock genes” at a specific cellular level. In the many mammalian and animal models, the master pacemaker is in the hypothalamus at the suprachiasmatic nucleus (SCN) that can regulate downstream oscillations in the peripheral tissues of the brain. The core clock genes are self- sustained and cell autonomous not only on the pace maker but also on the other dissociated cultured cells and peripheral tissues. Here we can review the general mechanisms involved in the clock genes that is responsible for the circadian rhythmicity in epileptic syndromes and these findings can elucidate the cell specific expression of the clock genes in different syndromes. In the recent past there has been considerable amount of progress in elucidating the molecular and cellular mechanisms that is involved in understand the core clock gene expression and the circadian rhythms effects on epileptic syndromes. However, there is very little understanding on how these two mechanisms interact to cause a core clock genes disruptions plays an important role. Recent studies in several animal models have shown the effects of time of the day on the neurophysiology and path-physiology in the epileptic syndrome. Together, these evidences from the past suggest that there can be a common mechanism underlying the circadian rhythmicity and epileptogenesis mechanism.

Blimp-1 molds the epigenetic architecture of IL-21-mediated autoimmune diseases through an autoregulatory circuit.

Positive regulatory domain 1 (PRDM1) encodes B lymphocyte–induced maturation protein 1 (BLIMP1), also known as a master regulator of T cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1–deficient T cells contribute to colitis in NOD mice. Reanalysis of published data sets also revealed an inverse correlation between PRDM1 and IL21 in Crohn’s disease. Here, we illustrate that Blimp-1 repressed IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf, from the Il21 promoter. Moreover, Blimp-1 overexpression–mediated reduction in permissive chromatin structures at the Il21 promoter could override IL-21–accelerated autoimmune diabetogenesis in small ubiquitin-like modifier–defective c-Maf–transgenic mice. An autoregulatory feedback loop to harness IL-21 expression was unveiled by the evidence that IL-21 addition induced time-dependent Blimp-1 expression and subsequently enriched its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, with IL-21R.Fc administration or IL-21 receptor deletion, attenuated Blimp-1 deficiency–mediated colitis and reinforced the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1–based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.

Circadian molecular clock disruption in chronic pulmonary diseases.

The circadian clock is the biochemical oscillator with a near 24-h period that is responsible for generating the circadian rhythms in peripheral organs including the lung. Mounting evidence suggests that circadian clock disruption during chronic lung diseases plays an essential role in augmented oxidative stress, inflammatory response, metabolic imbalances, hypoxia/hyperoxia, mucus secretion, dysregulated autophagy, and alters pulmonary function. Here, we review circadian clock disruption and discuss candidate clock genes that are altered at the transcriptional or translational level in chronic pulmonary diseases. This review aims to provide the current knowledge and understanding of the circadian molecular clock disruption in chronic pulmonary diseases which will further advance the development of novel clock-based therapeutics in the future.

Are M1 and M2 macrophages Effectual Players in Pathological Conditions?

Pathologic inflammatory conditions are frequently correlated with dynamic alterations through macrophage activation, with classically activated M1 cells associated with promoting and sustaining inflammation and M2 cells implicated in resolving or smoldering chronic inflammation. Inflammation is a common feature of various chronic diseases, and it has direct involvement in the emergence and progression of these conditions. Macrophages participate in an autoregulatory loop characterizing inflammatory process, as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during inflammation. Therefore, balancing the ratio of M1/M2 macrophages can help to ameliorate the inflammatory landscape of pathological conditions. This review will explore the role of macrophage polarization in distant pathological inflammatory conditions, such as cancer, autoimmunity, renal inflammation, stroke, and atherosclerosis, while sharing macrophage-driven pathogenesis.

LHX2 Regulates Shh Expression in the Limb Independent of the ZPA Regulatory Sequence

During limb development, proximal‐distal patterning is controlled by fibroblast growth factors (FGFs) secreted from the apical ectodermal ridge (AER), while anterior‐posterior expansion is coordinated by sonic hedgehog (SHH) released from the zone of polarizing activity (ZPA). Both FGFs and SHH regulate each other through an autoregulatory loop. The transcription factor LIM homeodomain 2 (LHX2) is an intermediate of the Fgf‐to‐Shh portion of the loop. In the absence of Lhx2 (and its redundant family member, Lhx9), Shh expression is markedly reduced. However, the mechanism by which LHX2 mediates FGF‐regulation of Shh is unclear. Shh is regulated by a limb‐specific enhancer called the ZPA Regulatory Sequence (ZRS). Using in silicoanalysis, our lab has identified two putative LHX2 binding sites within the ZRS. We hypothesized that LHX2 regulates Shh expression directly via the ZRS. To determine if LHX2 binding sites were necessary for ZRS activity, we mutated both LHX2 binding sites within a control tk‐ZRS‐eGFP reporter construct using site‐directed mutagenesis. We electroporated these constructs into the presumptive limb buds of chicken embryos (Hamburger‐Hamilton stage 14) and assessed for changes in ZRS activity in the limb buds 48 hours post transfection via fluorescence microscopy. We found that the mutation of both LHX2 binding sites within the ZRS resulted in activity similar to our control. These results suggest that LHX2 may not bind directly to the ZRS in its regulation of Shh. Instead, LHX2 may use another pathway to regulate Shhexpression. Further experiments are needed to confirm this connection. Investigating the mechanism by which LHX2 regulates Shh will provide insight into how LHX2 contributes to coordinated patterned‐limb development.

Regulation of LIM homeodomain 2 (Lhx2) in the distal limb bud during patterning and development

During limb morphogenesis, fibroblast growth factors (Fgfs) secreted from the apical ectodermal ridge (AER) direct proximodistal outgrowth of the limb, while sonic hedgehog (Shh) released from the zone of polarizing activity modulate anteroposterior expansion of the limb. Fgfs and Shh maintain each other’s expression through an autoregulatory loop. The transcription factor LIM homeodomain 2 (Lhx2) is expressed in the distal sub‐AER mesoderm and is important for Shh expression. We have identified a chicken enhancer upstream of the LHX2 promoter that is active in the distal sub‐AER LHX2 expression domain that contains putative transcription factor binding sites for known downstream targets of FGF signaling that are critical for activity. Therefore, we hypothesized that LASARM1 interacts with the LHX2 promoter and that FGF works through LASARM1 to regulate LHX2 expression. To determine this, we performed chromosome conformation capture (3C) on cells isolated from distal chicken limb buds and compared them to non‐LHX2 expressing tail cells. Promoter and enhancer specific primers were used to isolate ligated promoter‐enhancer fragments by end‐point PCR. Amplified sequences were then sequence validated. A 3C ligation product library was used as a control. We also evaluated the role of FGF to regulate LASARM1 activity in subAER mesoderm by analyzing LASARM1 activity following inhibition of FGF signaling by an FGF‐receptor inhibitor. End‐point PCR revealed promoter‐enhancer ligated amplicons in distal limb bud cells, but not in tail cells. DNA sequencing of enhancer‐ligated fragments confirmed LHX2‐LASARM1 fusion fragments for distal limb bud cells. Interestingly, disruption of FGF signaling via a specific FGF receptor inhibitor did not alter LASARM1 activity, although LHX2 expression was markedly reduced. These findings suggest that LASARM1 interacts with the LHX2 promoter during limb patterning, but additional enhancers are required to mediate the FGF‐mediated up‐regulation of LHX2. Evaluation of additional LHX2 enhancers is underway. Investigations regarding the relationship between FGF and LHX2 will provide important insights into the mechanisms underlying LHX2 regulation and the FGF‐to‐SHH reciprocal loop.

Phosphorylation regulates E3 ligase activity of Mdm2

The Mdm2 oncogene is associated with the negative regulation of the tumor suppressor p53 in an autoregulatory feedback loop in response to DNA damage. It has been assumed that Mdm2 functions in this pathway as an E3 ubiquitin ligase and is Mdm2’s principal function under all conditions. However, the E3 ligase activity can function either as ubiquitin or nedd8 E3 ligase. This activity is dependent on specific tyrosine kinases that are activated in response to DNA damage signaling or growth factor signaling pathways. The E3 ligase activity can have a distinct effect on the substrate by either stabilizing or signaling destruction. In the context of growth signaling pathways, we show that Src phosphorylation of Mdm2 recruits Ubc12 (nedd8 E2 enzyme). This results in the neddylation of the tumor suppressors pVHL and p53. The neddylation of pVHL prevents the association with p53, thereby attenuating the induction of anti‐angiogenic genes. The phosphorylation of Mdm2 by Src is in the Zinc domain, and we found that this domain is a key regulatory domain for the recruitment of E2 enzymes. These findings suggest that the role of Mdm2 is more complex than just functioning as an E3 ubiquitin ligase to signal for the destruction of p53.

The Host CYP1A1-Microbiota Metabolic Axis Promotes Gut Barrier Disruption in Methicillin-Resistant Staphylococcus aureus-Induced Abdominal Sepsis.

BackgroundHost-microbiota crosstalk has been implicated in multiple host metabolic pathway axes that regulate intestinal barrier function. Although constitutive cytochrome P4501A1 (CYP1A1) expression perturbs the microbiome-derived autoregulatory loop following enteric infection, little is known about the role of host CYP1A1 in modulating gut microbiome-mediated signaling during methicillin-resistant Staphylococcus aureus (MRSA)-induced abdominal sepsis and its effects on intestinal barrier integrity.MethodsAbdominal sepsis was induced by the intraperitoneal injection of MRSA in mice. The effect of CYP1A1 deficiency on gut barrier integrity was investigated using RNA sequencing, microbiome analyses, and targeted metabolomics. The microbiota-produced metabolites were validated in patients with sepsis and persistent MRSA infection.ResultsMice lacking CYP1A1 exhibited an altered gut microbiome, a reduced metabolic shift from lysine to cadaverine in the caecal contents and antimicrobial molecule production (Retnlb, Gbp7, and Gbp3), and they were protected against gut barrier disruption when subjected to MRSA challenge. These beneficial effects were validated in aryl hydrocarbon receptor (AHR) knockout (KO) mice by cohousing with CYP1A1 KO mice and abrogated after supplementation with cadaverine or Enterococcus faecalis, the primary microbiota genus for cadaverine synthesis. Antibiotic-driven gut dysbacteriosis impaired the survival benefit and disrupted the intestinal barrier integrity in CYP1A1 KO mice after MRSA infection. Furthermore, increased cadaverine levels in feces and serum were detected in critically ill patients with gut leakiness during persistent MRSA infection, whereas cadaverine was not detected in healthy controls. Additionally, microbiota-derived cadaverine induced enterocyte junction disruption by activating the histamine H4 receptor/nuclear factor-κB/myosin light-chain kinase signaling pathway.ConclusionThis study revealed the unexpected function of host CYP1A1 in microbiota-mediated cadaverine metabolism, with crucial consequences for dysbacteriosis following MRSA-induced abdominal sepsis, indicating that inhibiting CYP1A1 or blocking cadaverine-histamine H4 receptor signaling could be a potential therapeutic target against abdominal sepsis.Clinical Trial Registration[http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1800018646].

Molecular expression of clock genes in central and peripheral tissues of white-rumped munia (Lonchura striata)

ABSTRACT To synchronize with the fluctuating environment, organisms have evolved an endogenous time tracking mechanism referred to as the biological clock(s). This clock machinery has been identified in almost all cells of vertebrates and categorized as central and peripheral clocks. In birds, three independent circadian clocks have been identified in the hypothalamus, the pineal and the retina which interact and generate circadian time at a functional level. However, there is a limited knowledge of molecular clockwork and integration between central and peripheral clocks in birds. Therefore, we studied the daily expression of clock genes (Bmal1, Clock, Per2, Cry1, Npas2, Rev-Erbα, E4bp4, Pparα, Hlf and Tef) in three central circadian clocks (hypothalamus, pineal and retina), other brain areas (cerebellum, optic tectum and telencephalon) and in the peripheral tissues (liver, intestine, muscle and blood) of white-rumped munia. Adult birds were exposed to equinox photoperiod (12 L:12D) for 2 weeks and were then sampled (N = 5 per time point) at six-time points (ZT1, ZT5, ZT9, ZT13, ZT17 and ZT21). Daily expressions of clock genes were studied using qPCR. We observed daily variations and tissue-specific expression patterns for clock genes. These results are consistent with the autoregulatory circadian feedback loop proposed for the mammalian system and thus suggest a conserved tissue-level circadian time generation in white-rumped munia.

Physiological tissue-specific and age-related reduction of mouse TDP-43 levels is regulated by epigenetic modifications.

ABSTRACTThe cellular level of TDP-43 (also known as TARDBP) is tightly regulated; increases or decreases in TDP-43 have deleterious effects in cells. The predominant mechanism responsible for the regulation of the level of TDP-43 is an autoregulatory negative feedback loop. In this study, we identified an in vivo cause-effect relationship between Tardbp gene promoter methylation and specific histone modification and the TDP-43 level in tissues of mice at two different ages. Furthermore, epigenetic control was observed in mouse and human cultured cell lines. In amyotrophic lateral sclerosis, the formation of TDP-43-containing brain inclusions removes functional protein from the system. This phenomenon is continuous but compensated by newly synthesized protein. The balance between sequestration and new synthesis might become critical with ageing, if accompanied by an epigenetic modification-regulated decrease in newly synthesized TDP-43. Sequestration by aggregates would then decrease the amount of functional TDP-43 to a level lower than those needed by the cell and thereby trigger the onset of symptoms.

Functions of animal microRNA-encoded peptides: the race is on!

Short open reading frame (sORF)-encoded peptides (SEPs) recently emerged as new key players in biology. Pioneering work first established that sORFs encoded by long non-coding RNAs (lncRNAs) are efficiently translated and produce functional peptides. In plants, primary transcripts of microRNAs (pri-miRNAs) also produce sORF-encoded peptides called miPEPs, which are involved in specific transcriptional autoregulatory feedback loops (Lauressergues etal, 2015). To what extend are such mechanisms conserved in other species, especially in animals? In this issue of EMBO reports, Zhou etal show that pri-miR-31 encodes a miPEP promoting Treg differentiation and downregulating pri-miR-31 expression (Zhou etal, 2022).