Domain Protein Family Research Articles

Comparative Proteome-Wide Abundance Profiling of Yeast Strains Deleted for Cdc48 Adaptors

The yeast ATPase Cdc48 (known as p97/VCP in human cells) plays an important role in the Ubiquitin Proteasome System. VCP is essential for cancer cell proliferation, and its dysregulation has been implicated in several neurodegenerative diseases. Cdc48 functions by extracting ubiquitylated proteins from membranes, protein complexes and chromatin by often facilitating their proteasomal degradation. Specific adaptors or cofactors, primarily belonging to the UBX domain-containing protein family (which has seven members in Saccharomyces cerevisiae) recruit Cdc48 to ubiquitylated proteins. Here, we employed sample multiplexing-based quantitative mass spectrometry to profile global protein abundance in p97 adaptor deletion strains, specifically comparing seven single deletion strains of UBX domain-containing proteins and the Cuz1 deletion strain, which belongs to the zinc finger AN1-type domain protein family. We observed that each strain showed unique sets of differentially abundant proteins compared to the wild type. Our analysis also revealed a role for Ubx3 in maintaining wild type levels of mitochondrial proteins. Overall, we identified ~1400 differentially abundant proteins in the absence of a specific Cdc48 adaptor. This unique dataset offers a valuable resource for studying the functions of these adaptors, aiming to achieve a better understanding of the cellular processes regulated by Cdc48 itself and to deepen our understanding of the Ubiquitin Proteasome System.

Exploring the unfolding pathways of protein families using Elastic Network Model

We explore how a protein’s native structure determines its unfolding process. We examine how the local structural features, like shear, and the global structural properties, like the number of soft modes, change during unfolding. Simulations are performed using a Gaussian Network Model (GNM) with bond breaking for both thermal and force-induced unfolding scenarios. We find that unfolding starts in areas of high shear in the native structure and progressively spreads to the low shear regions. Interestingly, analysis of single domain protein families (Chymotrypsin inhibitor and Barnase) reveal that proteins with distinct unfolding pathways exhibit divergent behavior of the number of soft modes during unfolding. This suggests that the number of soft modes might be a valuable tool for understanding thermal unfolding pathways. Additionally, we found a strong link between a protein’s overall structural similarity (TM-score) and its unfolding pathways, highlighting the importance of the native structure in determining how a protein unfolds.

Arabidopsis B-BOX DOMAIN PROTEIN14/15/16 form a feedback loop with ELONGATED HYPOCOTYL 5 and PHYTOCHROME-INTERACTING FACTORs to regulate hypocotyl elongation

Light-regulated developmental processes such as photomorphogenesis and flowering play important roles in the plant life cycle, from seedling emergence to reproduction. Three members of the Arabidopsis thaliana B-BOX DOMAIN PROTEIN (BBX) family, BBX14, BBX15, and BBX16 (hereafter BBX14/15/16), redundantly regulate flowering time, but whether this genetic redundancy also affects the regulation of photomorphogenesis remains unclear. Here, we show that light induces BBX14/15/16 expression primarily in the hypocotyl, where BBX14/15/16 redundantly repress hypocotyl elongation. PHYTOCHROME-INTERACTING FACTORs (PIFs) negatively regulate BBX14/15/16 expression mainly through GOLDEN-LIKE proteins (GLKs); however, analyses of ChIP-seq data showed that PIFs are recruited to the BBX14/15/16 loci and can also regulate these genes independently of GLKs. ELONGATED HYPOCOTYL 5 (HY5), a major regulator of photomorphogenesis, also directly binds to the BBX14/15/16 loci and regulates their expression. Simultaneous knockdown of BBX14/15/16 resulted in significant downregulation of HY5 and upregulation of PIFs, suggesting that these factors participate in a feedback regulatory loop. Indeed, BBX14/15/16 induced HY5 promoter activity by binding to the HY5 promoter. The brassinosteroid-responsive gene TOUCH4 (TCH4) and several auxin-responsive SMALL AUXIN UPREGULATED RNA (SAUR) genes were upregulated in the BBX14/15/16 knockdown plants, suggesting that auxin and brassinosteroids might participate in BBX14/15/16-mediated hypocotyl regulation. Mutating the predicted BBX-binding sites in SAUR4 and TCH4 impaired their regulation by BBX14/15/16. We propose that BBX14/15/16, together with HY5 and PIFs, form a feedback loop that regulates the expression of auxin- and brassinosteroid-related genes to modulate hypocotyl elongation.

249 (PB237): The bromodomain and extraterminal domain family proteins, BRD2, BRD3 and BRD4, are enrolled in H19-dependent transcriptional regulation of cell adhesion molecules and modulate metastatic dissemination program in prostate cancer

249 (PB237): The bromodomain and extraterminal domain family proteins, BRD2, BRD3 and BRD4, are enrolled in H19-dependent transcriptional regulation of cell adhesion molecules and modulate metastatic dissemination program in prostate cancer

N6-Methyladenosine Positively Regulates Coxsackievirus B3 Replication.

Enteroviruses such as coxsackievirus B3 are identified as a common cause of viral myocarditis, but the potential mechanism of its replication and pathogenesis are largely unknown. The genomes of a variety of viruses contain N6-methyladenosine (m6A), which plays important roles in virus replication. Here, by using the online bioinformatics tools SRAMP and indirect immunofluorescence assay (IFA), we predict that the CVB3 genome contains m6A sites and found that CVB3 infection could alter the expression and cellular localization of m6A-related proteins. Moreover, we found that 3-deazaadenosine (3-DAA), an m6A modification inhibitor, significantly decreased CVB3 replication. We also observed that the m6A methyltransferases methyltransferase-like protein 3 (METTL3) and METTL14 play positive roles in CVB3 replication, whereas m6A demethylases fat mass and obesity-associated protein (FTO) or AlkB homolog 5 (ALKBH5) have opposite effects. Knockdown of the m6A binding proteins YTH domain family protein 1 (YTHDF1), YTHDF2 and YTHDF3 strikingly decreased CVB3 replication. Finally, the m6A site mutation in the CVB3 genome decreased the replication of CVB3 compared with that in the CVB3 wild-type (WT) strain. Taken together, our results demonstrated that CVB3 could exploit m6A modification to promote viral replication, which provides new insights into the mechanism of the interaction between CVB3 and the host.

Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.

Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity.

The bromodomain and extraterminal domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor because of an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, bromodomain-containing protein 4 (BRD4) binds to estrogen receptor binding sites and activates transcription of critical oncogenes such as MYC, independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator reduces BRD4's enhancer occupancy. Profiling changes of the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6 and the polymerase-associated factor 1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.

Genome-Wide Characterization of IQD Family Proteins in Apple and Functional Analysis of the Microtubule-Regulating Abilities of MdIQD17 and MdIQD28 under Cold Stress.

Microtubules undergo dynamic remodeling in response to diverse abiotic stress in plants. The plant-specific IQ67 DOMAIN (IQD) family proteins serve as microtubule-associated proteins, playing multifaceted roles in plant development and response to abiotic stress. However, the biological function of IQD genes in apple remains unclear. In this study, we conducted a comprehensive analysis of the Malus domestica genome, identifying 42 IQD genes distributed across 17 chromosomes and categorized them into four subgroups. Promoter analysis revealed the presence of stress-responsive elements. Subsequent expression analysis highlighted the significant upregulation of MdIQD17 and MdIQD28 in response to cold treatments, prompting their selection for further functional investigation. Subcellular localization studies confirmed the association of MdIQD17 and MdIQD28 with microtubules. Crucially, confocal microscopy and quantification revealed diminished microtubule depolymerization in cells transiently overexpressing MdIQD17 and MdIQD28 compared to wild-type cells during cold conditions. In conclusion, this study provides a comprehensive analysis of IQD genes in apple, elucidating their molecular mechanism in response to cold stress.

Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m6A modification

BackgroundDysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration.MethodsWe investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples.ResultsIncreased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues.ConclusionsWe describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.Graphical abstract

Novel inhibitors of bromodomain and extra-terminal domain trigger cell death in breast cancer cell lines

Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies.

BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1–3 promoter, resulting in the suppression of E2F1–3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1–3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1–3 promoters, enhancing E2F1–3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.

Zebrafish phd1 enhances mavs-mediated antiviral responses in a hydroxylation-independent manner.

PHD1 is a member of the prolyl hydroxylase domain protein (PHD1-4) family, which plays a prominent role in the post-translational modification of its target proteins by hydroxylating proline residues. The best-characterized targets of PHD1 are hypoxia-inducible factor α (HIF-1α and HIF-2α), two master regulators of the hypoxia signaling pathway. In this study, we show that zebrafish phd1 positively regulates mavs-mediated antiviral innate immunity. Overexpression of phd1 enhances the cellular antiviral response. Consistently, zebrafish lacking phd1 are more susceptible to spring viremia of carp virus infection. Further assays indicate that phd1 interacts with mavs through the C-terminal transmembrane domain of mavs and promotes mavs aggregation. In addition, zebrafish phd1 attenuates K48-linked polyubiquitination of mavs, leading to stabilization of mavs. However, the enzymatic activity of phd1 is not required for phd1 to activate mavs. In conclusion, this study reveals a novel function of phd1 in the regulation of antiviral innate immunity.IMPORTANCEPHD1 is a key regulator of the hypoxia signaling pathway, but its role in antiviral innate immunity is largely unknown. In this study, we found that zebrafish phd1 enhances cellular antiviral responses in a hydroxylation-independent manner. Phd1 interacts with mavs through the C-terminal transmembrane domain of mavs and promotes mavs aggregation. In addition, phd1 attenuates K48-linked polyubiquitination of mavs, leading to stabilization of mavs. Zebrafish lacking phd1 are more susceptible to spring viremia of carp virus infection. These findings reveal a novel role for phd1 in the regulation of mavs-mediated antiviral innate immunity.

A Novel BD2-Selective Inhibitor of BRDs Mitigates ROS Production and OA Pathogenesis.

Bromodomain and extra-terminal domain (BET) family proteins regulate transcription and recognize lysine residues in histones. Selective BET inhibitors targeting one domain have attracted attention because they maintain normal physiological activities, whereas pan (nonselective) BET inhibitors do not. Osteoarthritis (OA) is a joint disorder characterized by cartilage degeneration for which no treatment currently exists. Here, we investigated whether the selective inhibition of BET proteins is an appropriate therapeutic strategy for OA. We focused on the development and characterization of 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (BBC0906), a novel bromodomain 2 (BD2)-specific inhibitor designed to suppress OA progression. Using a DNA-encoded chemical library (DEL) screening approach, BBC0906 was identified because of its high affinity with the BD2 domain of BET proteins. BBC0906 effectively reduced reactive oxygen species (ROS) production and suppressed catabolic factor expression in chondrocytes in vitro. Moreover, in an OA mouse model induced by the destabilization of the medial meniscus (DMM), BBC0906 intra-articular injection attenuated cartilage degradation and alleviated OA. Importantly, BBC0906 selectively inhibits the BD2 domain, thus minimizing its potential side effects. We highlighted the therapeutic potential of targeting BET proteins to modulate oxidative stress and suppress cartilage degradation in OA. BBC0906 is a promising candidate for OA treatment, offering improved safety and efficacy.

The YTH domain-containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets.

The modification of N6-methyladenosine (m6A) plays a pivotal role in tumor by altering both innate and adaptive immune systems through various pathways, including the regulation of messenger RNA. The YTH domain protein family, acting as "readers" of m6A modifications, affects RNA splicing, stability, and immunogenicity, thereby playing essential roles in immune regulation and antitumor immunity. Despite their significance, the impact of the YTH domain protein family on tumor initiation and progression, as well as their involvement in tumor immune regulation and therapy, remains underexplored and lacks comprehensive review. This review introduces the molecular characteristics of the YTH domain protein family and their physiological and pathological roles in biological behavior, emphasizing their mechanisms in regulating immune responses and antitumor immunity. Additionally, the review discusses the roles of the YTH domain protein family in immune-related diseases and tumor resistance, highlighting that abnormal expression or dysfunction of YTH proteins is closely linked to tumor resistance. This review provides an in-depth understanding of the YTH domain protein family in immune regulation and antitumor immunity, suggesting new strategies and directions for immunotherapy of related diseases. These insights not only deepen our comprehension of m6A modifications and YTH protein functions but also pave the way for future research and clinical applications.

Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage.

Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro. Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo. In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro. Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.

Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity.

The Bromodomain and Extra-Terminal Domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor due to an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, BRD4 binds to estrogen receptor binding sites and activates transcription of critical oncogenes independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator complex reduces BRD4's enhancer occupancy. Profiling changes in the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6, and PAF1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.

A novel PROTAC molecule dBET1 alleviates pathogenesis of experimental autoimmune encephalomyelitis in mice by degrading BRD4

Neuroinflammation and neurodegeneration are hallmarks of multiple sclerosis (MS). Bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) protein family member, is indispensable for the transcription of pro-inflammatory genes. Therefore, inhibiting BRD4 may be a prospective therapeutic approach for modulating the inflammatory response and regulating the course of MS. dBET1, a newly synthesized proteolysis-targeting chimera (PROTAC), exhibits effectively degrades of BRD4. However, the precise effects of dBET1 on MS require further investigation. Therefore, we assessed the effect of dBET1 in experimental autoimmune encephalomyelitis (EAE), a typical MS experimental model. Our findings revealed that BRD4 is mainly expressed in astrocytes and neurons of the spinal cords, and is up-regulated in the spinal cords of EAE mice. The dBET1 attenuated lipopolysaccharide-induced expression of astrocytic pro-inflammatory mediators and inhibited deleterious molecular activity in astrocytes. Correspondingly, dBET1, used in preventive and therapeutic settings, alleviated the behavioral symptoms in EAE mice, as demonstrated by decreased demyelination, alleviated leukocyte infiltration, reduced microglial and astrocyte activation, and diminished inflammatory mediator levels. In addition, dBET1 corrected the imbalance in peripheral T cells and protected blood–brain barrier integrity in EAE mice. The underlying mechanism involved suppressing the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase /extracellular signal-regulated kinase, and nuclear factor kappa B pathways. In summary, our data strongly suggests that dBET1 is a promising treatment option for MS.

YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8+ T lymphocytes

Immune evasion is one of the critical hallmarks of malignant tumors, especially non-small cell lung cancer (NSCLC). Emerging findings have illustrated the roles of N6-methyladenosine (m6A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m6A reader YTH domain family protein 3 (YTHDF3) on NSCLC immune evasion. YTHDF3 was found to be highly expressed in NSCLC tissue and act as an independent prognostic factor for overall survival. Functionally, up-regulation of YTHDF3 impaired the CD8+ T antitumor activity to deteriorate NSCLC immune evasion, while YTHDF3 silencing recovered the CD8+ T antitumor activity to inhibit immune evasion. Besides, YTHDF3 up-regulation reduced the apoptosis of NSCLC cells. Mechanistically, PD-L1 acted as the downstream target for YTHDF3, and YTHDF3 could upregulate the transcription stability of PD-L1 mRNA. Overall, YTHDF3 targeted PD-L1 to promote NSCLC immune evasion partially through escaping effector cell cytotoxicity CD8+ T mediated killing and antitumor immunity. In summary, this study provides an essential insight for m6A modification on CD8+ T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.

A Review of the Bromodomain and Extraterminal Domain Epigenetic Reader Proteins: Function on Virus Infection and Cancer.

The BET (bromodomain and extraterminal domain) family of proteins, particularly BRD4 (bromodomain-containing protein 4), plays a crucial role in transcription regulation and epigenetic mechanisms, impacting key cellular processes such as proliferation, differentiation, and the DNA damage response. BRD4, the most studied member of this family, binds to acetylated lysines on both histones and non-histone proteins, thereby regulating gene expression and influencing diverse cellular functions such as the cell cycle, tumorigenesis, and immune responses to viral infections. Given BRD4's involvement in these fundamental processes, it is implicated in various diseases, including cancer and inflammation, making it a promising target for therapeutic development. This review comprehensively explores the roles of the BET family in gene transcription, DNA damage response, and viral infection, discussing the potential of targeted small-molecule compounds and highlighting BET proteins as promising candidates for anticancer therapy.

Adolescent co-exposure to environmental cadmium and high-fat diet induces cognitive decline via Larp7 m6A-mediated SIRT6 inhibition

The effects and underlying mechanisms of adolescent exposure to combined environmental hazards on cognitive function remain unclear. Here, using a combined exposure model, we found significant cognitive decline, hippocampal neuronal damage, and neuronal senescence in mice exposed to cadmium (Cd) and high-fat diet (HFD) during adolescence. Furthermore, we observed a significant downregulation of Sirtuin 6 (SIRT6) expression in the hippocampi of co-exposed mice. UBCS039, a specific SIRT6 activator, markedly reversed the above adverse effects. Further investigation revealed that co-exposure obviously reduced the levels of La ribonucleoprotein 7 (LARP7), disrupted the interaction between LARP7 and SIRT6, ultimately decreasing SIRT6 expression in mouse hippocampal neuronal cells. Overexpression of Larp7 reversed the combined exposure-induced SIRT6 decrease and senescence in mouse hippocampal neuronal cells. Additionally, the results showed notably elevated levels of Larp7 m6A and YTH domain family protein 2 (YTHDF2) in mouse hippocampal neuronal cells treated with the combined hazards. Ythdf2 short interfering RNA, RNA immunoprecipitation, and RNA stability assays further demonstrated that YTHDF2 mediated the degradation of Larp7 mRNA under combined exposure. Collectively, adolescent co-exposure to Cd and HFD causes hippocampal senescence and cognitive decline in mice by inhibiting LARP7-mediated SIRT6 expression in an m6A-dependent manner.