Homeobox Research Articles

Functional characterization of WsPR-1 reveals its interplay with cytokinin and gibberellin signaling pathways

Pathogenesis-related protein 1 (PR-1) is an antimicrobial protein involved in systemic acquired resistance (SAR) in plants, but its regulatory role and interactions with other pathways remain unclear. In this study, we functionally characterize WsPR-1 gene of Withania somnifera in Nicotiana tabacum to elucidate its role in plant defense, growth, and development. Interestingly, transgenic tobacco plants with increased levels of cytokinin (CK) and decreased gibberellins (GAs) exhibited stunted shoot growth, an underdeveloped root system, modified leaf morphology, reduced seed pod production, and delayed leaf senescence. Transcriptional analysis revealed that WsPR-1 overexpression downregulated the GA 20-oxidase (GA20ox) gene involved in GA biosynthesis while upregulating GA 2-oxidase (GA2ox), a GA catabolic enzyme. Moreover, transcript levels of FRUITFULL (FUL) and LEAFY (NFL2) flowering genes exhibited a decrease in WsPR-1 plants, which could explain the delayed flowering and reduced seed pod development in transgenic plants. Confocal microscopy confirmed increased lignin deposition in stem cross-sections of WsPR-1 transgenic plants, supported by gene expression analysis and lignin content quantification. Additionally, our findings also suggest the involvement of Knotted1-like homeobox (KNOX) gene in enhancing cytokinin levels. This study highlights PR-1's regulatory role in plant growth and development, with potential to boost crop yields and enhance resilience.

Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation.

SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2CD/CD and Setd2-/- mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2-/-, the Setd2CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5' Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.

Prognostic Significance of Caudal-type Homeobox Gene 2 and Sex-determining Region Y-Box 2 Immunohistochemistry Markers in Gastric Cancer – A Clinicopathological Study

Abstract Background: Gastric cancer is one of the most commonly diagnosed cancers and the third leading cause of cancer-related deaths in the world as it has a poor prognosis due to its delayed presentation. Adenocarcinoma (intestinal or diffuse type) is the most common type histologically, and tumor, node, and metastasis staging is essential for prognosis and treatment planning. Gastric cancer patients may have different clinical presentation even within the same cancer stage group, hence it is important to evaluate additional markers in such patients which can help in prognosticating them to aid in effective management of such patients. This study evaluates two new immunohistochemistry (IHC) markers and their clinical correlation which will help in prognosticating gastric cancer patients. Materials and Methods: Biopsy tissues from 30 patients between April 2016 and April 2019, who underwent upper gastrointestinal endoscopy in a tertiary care center of Armed Forces and were found to have gastric cancer, were studied. Caudal-type homeobox gene 2 (CDX2) and sex-determining region Y-box 2 (SOX2) immunoreactivity was correlated with histomorphology, clinical presentation, and staging of tumor. Results: CDX2 positivity (P = 0.002) as well as SOX2 negativity (P = 0.058) was associated with an advanced stage of disease in our study. CDX2+/SOX2− profile was also noted to be statistically correlating (P = 0.014) with poor prognosis in gastric cancer. Conclusion: Loss of SOX2 together with positive CDX2 expression had a good correlation with advanced disease and poor outcome. Further studies should be undertaken for targeted therapy for these IHC markers.

Members of an array of zinc finger proteins specify distinct Hox chromatin boundaries.

Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type specific gene expression patterns. While this partitioning is reconstructed during differentiation, the chromatin occupancy of the key insulator, CTCF, is unchanged at the developmentally important Hox clusters. Thus, dynamic changes in chromatin boundaries must entail other activities. Given its requirement for chromatin loop formation, we examined cohesin-based chromatin occupancy without known insulators, CTCF and MAZ, and identified a family of zinc finger proteins (ZNFs), some of which exhibit tissue-specific expression. Two such ZNFs foster chromatin boundaries at the Hox clusters that are distinct from each other and from MAZ. PATZ1 was critical to the thoracolumbar boundary in differentiating motor neurons and mouse skeleton, while ZNF263 contributed to cervicothoracic boundaries. We propose that these insulating activities act with cohesin, alone or combinatorially, with or without CTCF, to implement precise positional identity and cell fate during development.

Changes in Serum HOXA9 , PCⅢ, SE-CAD Levels in AML Patients after Chemotherapy with DCAG Regimen and Their Relationship with Prognosis

To investigate the changes in serum homeobox A9 (HOXA9 ), soluble E-cadherin (SE-CAD) and type Ⅲ procollagen (PCⅢ) levels in acute myeloid leukemia (AML) patients after chemotherapy with DCAG regimen and their relationship with prognosis. The clinical data of 80 patients with relapsed/refractory AML diagnosed and treated in our hospital from March 2018 to December 2021 were retrospectively analyzed. According to different treatment regimen, the patients were divided into DCAG group (n=40) and CAG group (n=40). The clinical efficacy and changes of HOXA9 , SE-CAD and PCⅢ levels before and after treatment were compared. In addition, all patients were divided into remission group (n=58) and non-remission group (n=22) according to the clinical efficacy. Univariate and multivariate analyses were performed to analyze the risk factors affecting the prognosis of AML patients. The predictive efficacy of the three single indicators, HOXA9 , SE-CAD, and PC III, and their combination on prognosis was analyzed. Compared with before treatment, the levels of HOXA9 , SE-CAD and PCⅢ in both the DCAG and CAG groups were decreased after treatment, and the improvement of each indicator and the clinical efficacy in the DCAG group were significantly better than those in the CAG group (all P < 0.05). Multivariate analysis showed that increased bone marrow blast count, HOXA9 mRNA, SE-CAD and PCⅢ levels were independent risk factors affecting the efficacy of chemotherapy in AML patients (all P < 0.05). ROC curves showed that the combination of HOXA9 mRNA, SE-CAD and PCIII could effectively predict the prognosis of AML patients, with a sensitivity of 84.80% and a specificity of 88.20%. DCAG regimen can significantly improve the levels of HOXA9 mRNA, SE-CAD and PCⅢ in AML patients, these three indicators are all independent risk factors affecting the prognosis of AML patients, and the combination of the three indicators can effectively predict the prognosis of the patients.

PHD17 acts as a target of miR1320 to negatively control cold tolerance via JA-activated signaling in rice

Plant Homeo Domain (PHD) proteins are involved in diverse biological processes during plant growth. However, the regulation of PHD genes on rice cold stress response remains largely unknown. Here, we reported that PHD17 negatively regulated cold tolerance in rice seedlings as a cleavage target of miR1320. PHD17 expression was greatly induced by cold stress, and was down-regulated by miR1320 overexpression and up-regulated by miR1320 knockdown. Through 5′RACE and dual luciferase assays, we found that miR1320 targeted and cleaved the 3′UTR region of PHD17. PHD17 was a nuclear-localized protein and acted as a transcriptional activator in yeast. PHD17 overexpression reduced cold tolerance of rice seedlings, while knockout of PHD17 increased cold tolerance, partially via the CBF cold signaling. By combining transcriptomic and physiological analyses, we demonstrated that PHD17 modulated ROS homeostasis and flavonoid accumulation under cold stress. K-means clustering analysis revealed that differentially expressed genes in PHD17 transgenic lines were significantly enriched in the jasmonic acid (JA) biosynthesis pathway, and expression of JA biosynthesis and signaling genes was verified to be affected by PHD17. Cold stress tests applied with MeJA or IBU (JA synthesis inhibitor) further suggested the involvement of PHD17 in JA-mediated cold signaling. Taken together, our results suggest that PHD17 acts downstream of miR1320 and negatively regulates cold tolerance of rice seedlings through JA-mediated signaling pathway.

Extreme genetic signatures of local adaptation in a notorious rice pest, Chilo suppressalis

ABSTRACT Climatic variation stands as a significant driving force behind genetic differentiation and the evolution of adaptive traits. Chilo (C.) suppressalis, commonly known as the rice stem borer, is a highly destructive pest that crucially harms rice production. The lack of natural population genomics data has hindered a more thorough understanding of its climate adaptation, particularly the genetic basis underlying adaptive traits. To overcome this obstacle, our study employed completely resequenced genomes of 384 individuals to explore the population structure, demographic history, and gene flow of C. suppressalis in China. This study observed that its gene flow occurred asymmetrically, moving from central populations to peripheral populations. Using genome-wide selection scans and genotype-environment association studies, we identified potential loci that may be associated with climatic adaptation. The most robust signal was found to be associated with cold tolerance, linked to a homeobox gene, goosecoid (GSC), whose expression level was significantly different in low and high latitudes. Moreover, downregulating the expression of this gene by RNAi enhances its cold tolerance phenotypes. Our findings have uncovered and delved into the genetic foundation of the ability of C. suppressalis to adapt to its environment. This is essential in ensuring the continued effectiveness and sustainability of novel control techniques.

A taxon-restricted duplicate of Iroquois3 is required for patterning the spider waist.

The chelicerate body plan is distinguished from other arthropod groups by its division of segments into 2 tagmata: the anterior prosoma ("cephalothorax") and the posterior opisthosoma ("abdomen"). Little is understood about the genetic mechanisms that establish the prosomal-opisthosomal (PO) boundary. To discover these mechanisms, we created high-quality genomic resources for the large-bodied spider Aphonopelma hentzi. We sequenced specific territories along the antero-posterior axis of developing embryos and applied differential gene expression analyses to identify putative regulators of regional identity. After bioinformatic screening for candidate genes that were consistently highly expressed in only 1 tagma (either the prosoma or the opisthosoma), we validated the function of highly ranked candidates in the tractable spider model Parasteatoda tepidariorum. Here, we show that an arthropod homolog of the Iroquois complex of homeobox genes is required for proper formation of the boundary between arachnid tagmata. The function of this homolog had not been previously characterized, because it was lost in the common ancestor of Pancrustacea, precluding its investigation in well-studied insect model organisms. Knockdown of the spider copy of this gene, which we designate as waist-less, in P. tepidariorum resulted in embryos with defects in the PO boundary, incurring discontinuous spider germ bands. We show that waist-less is required for proper specification of the segments that span the prosoma-opisthosoma boundary, which in adult spiders corresponds to the narrowed pedicel. Our results demonstrate the requirement of an ancient, taxon-restricted paralog for the establishment of the tagmatic boundary that defines Chelicerata.

Age-associated growth control modifies leaf proximodistal symmetry and enabled leaf shape diversification

Biological shape diversity is often manifested in modulation of organ symmetry and modification of the patterned elaboration of repeated shape elements.1,2,3,4,5 Whether and how these two aspects of shape determination are coordinately regulated is unclear.5,6,7 Plant leaves provide an attractive system to investigate this problem, because they often show asymmetries along the proximodistal (PD) axis of their blades, along which they can also produce repeated marginal outgrowths such as serrations or leaflets.1 One aspect of leaf shape diversity is heteroblasty, where the leaf form in a single genotype is modified with progressive plant age.8,9,10,11 In Arabidopsis thaliana, a plant with simple leaves, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9 (SPL9) controls heteroblasty by activating CyclinD3 expression, thereby sustaining proliferative growth and retarding differentiation in adult leaves.12,13 However, the precise significance of SPL9 action for leaf symmetry and marginal patterning is unknown. By combining genetics, quantitative shape analyses, and time-lapse imaging, we show that PD symmetry of the leaf blade in A.thaliana decreases in response to an age-dependent SPL9 expression gradient, and that SPL9 action coordinately regulates the distribution and shape of marginal serrations and overall leaf form. Using comparative analyses, we demonstrate that heteroblastic growth reprogramming in Cardamine hirsuta, a complex-leafed relative of A.thaliana, also involves prolonging the duration of cell proliferation and delaying differentiation. We further provide evidence that SPL9 enables species-specific action of homeobox genes that promote leaf complexity. In conclusion, we identified an age-dependent layer of organ PD growth regulation that modulates leaf symmetry and has enabled leaf shape diversification.

Goosecoid promotes pancreatic adenocarcinoma metastasis through TGF-β signaling.

Goosecoid (GSC), translated from a homeobox gene, is a protein that participates in metastasis of various cancers. Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies associated with a poor diagnosis and prognosis. To develop new treatment target or biomarker for PAAD, this study intended to assess the effects and the molecular mechanism of GSC on PAAD metastasis. The expressive discrepancy of GSC in PAAD and normal tissues/cells was compared by both the quantitative PCR and western blot. The effects of GSC silencing and GSC over-expression on PAAD cells and TGF-β signaling were proved by wound-healing assay, cell counting kit-8, Transwell assay and western blot. From the results, GSC mRNA and protein levels were enriched in PAAD cancer tissues and cells. GSC silencing prohibited metastasis of PAAD cells including the ability to invade, migrate and epithelial-mesenchymal transition (EMT), whereas GSC upregulation stimulated these cells behaviors above. GSC silencing reversed the effects on cellular processes induced by activation of the TGF-β pathway. Furthermore, silencing of GSC postponed tumor growth in xenograft model. In summary, GSC was abundantly expressed in PAAD, which activated the TGF-β pathway to enhance cell metastasis and tumor development.

Evolutionary patterns and functional effects of 3D chromatin structures in butterflies with extensive genome rearrangements

Chromosome rearrangements may distort 3D chromatin architectures and thus change gene regulation, yet how 3D chromatin structures evolve in insects is largely unknown. Here, we obtain chromosome-level genomes for four butterfly species, Graphium cloanthus, Graphium sarpedon, Graphium eurypylus with 2n = 30, 40, and 60, respectively, and Papilio bianor with 2n = 60. Together with large-scale Hi-C data, we find that inter-chromosome rearrangements very rarely disrupted the pre-existing 3D chromatin structure of ancestral chromosomes. However, some intra-chromosome rearrangements changed 3D chromatin structures compared to the ancestral configuration. We find that new TADs and subTADs have emerged across the rearrangement sites where their adjacent compartments exhibit uniform types. Two intra-chromosome rearrangements altered Rel and lft regulation, potentially contributing to wing patterning differentiation and host plant choice. Notably, butterflies exhibited chromatin loops between Hox gene cluster ANT-C and BX-C, unlike Drosophila. Our CRISPR-Cas9 experiments in butterflies confirm that knocking out the CTCF binding site of the loops in BX-C affected the phenotypes regulated by Antp in ANT-C, resulting in legless larva. Our results reveal evolutionary patterns of insect 3D chromatin structures and provide evidence that 3D chromatin structure changes can play important roles in the evolution of traits.

Combined detection of SHOX2 and PTGER4 methylation with serum marker CYFRA21-1 for improved diagnosis of malignant pleural mesothelioma

AimsTo investigate the performance of a combined biomarker approach using the methylation status of the short stature homeobox 2 (SHOX2) and prostaglandin E2 receptor EP4 (PTGER4) genes, along with the...

Genome mining of WOX-ARF gene linkage in Machilus pauhoi underpinned cambial activity associated with IAA induction.

As an upright tree with multifunctional economic application, Machilus pauhoi is an excellent choice in modern forestry from Lauraceae. The growth characteristics is of great significance for its molecular breeding and improvement. However, there still lack the information of WUSCHEL-related homeobox (WOX) and Auxin response factor (ARF) gene family, which were reported as specific transcription factors in plant growth as well as auxin signaling. Here, a total of sixteen MpWOX and twenty-one MpARF genes were identified from the genome of M. pauhoi. Though member of WOX conserved in the Lauraceae, MpWOX and MpARF genes were unevenly distributed on 12 chromosomes as a result of region duplication. These genes presented 45 and 142 miRNA editing sites, respectively, reflecting a potential post-transcriptional restrain. Overall, MpWOX4, MpWOX13a, MpWOX13b, MpARF6b, MpARF6c, and MpARF19a were highly co-expressed in the vascular cambium, forming a working mode as WOX-ARF complex. MpWOXs contains typical AuxRR-core and TGA-element cis-acting regulatory elements in this auxin signaling linkage. In addition, under IAA and NPA treatments, MpARF2a and MpWOX1a was highly sensitive to IAA response, showing significant changes after 6 hours of treatment. And MpWOX1a was significantly inhibited by NPA treatment. Through all these solid analysis, our findings provide a genetic foundation to growth mechanism analysis and further molecular designing breeding in Machilus pauhoi.

Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia.

Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.

PagKNAT2/6b regulates tension wood formation and gravitropism by targeting cytokinin metabolism.

Tension wood is a specialized xylem tissue associated with gravitropism in angiosperm trees. However, few regulators of tension wood formation have been identified. The molecular mechanisms underpinning tension wood formation remain elusive. Here, we report that a Populus KNOTTED-like homeobox gene, PagKNAT2/6b, is involved in tension wood formation and gravity response. Transgenic poplar plants overexpressing PagKNAT2/6b displayed more sensitive gravitropism than controls, as indicated by increased stem curvature. Microscopic examination revealed greater abundance of fibre cells with a gelatinous cell wall layer (G-layer) and asymmetric growth of secondary xylem in PagKNAT2/6b overexpression lines. Conversely, PagKNAT2/6b dominant repression plants exhibited decreased tension wood formation and reduced response to gravity stimulation. Moreover, sensitivity to gravity stimulation showed a negative relationship with development stage. Expression of genes related to growth and senescence was affected in PagKNAT2/6b transgenic plants. More importantly, transcription activation and electrophoretic mobility shift assays suggested that PagKNAT2/6b promotes the expression of cytokinin metabolism genes. Consistently, cytokinin content was increased in PagKNAT2/6b overexpression plants. Therefore, PagKNAT2/6b is involved in gravitropism and tension wood formation, likely via modulation of cytokinin metabolism.

The brittle star genome illuminates the genetic basis of animal appendage regeneration

Species within nearly all extant animal lineages are capable of regenerating body parts. However, it remains unclear whether the gene expression programme controlling regeneration is evolutionarily conserved. Brittle stars are a species-rich class of echinoderms with outstanding regenerative abilities, but investigations into the genetic bases of regeneration in this group have been hindered by the limited genomic resources. Here we report a chromosome-scale genome assembly for the brittle star Amphiura filiformis. We show that the brittle star genome is the most rearranged among echinoderms sequenced so far, featuring a reorganized Hox cluster reminiscent of the rearrangements observed in sea urchins. In addition, we performed an extensive profiling of gene expression during brittle star adult arm regeneration and identified sequential waves of gene expression governing wound healing, proliferation and differentiation. We conducted comparative transcriptomic analyses with other invertebrate and vertebrate models for appendage regeneration and uncovered hundreds of genes with conserved expression dynamics, particularly during the proliferative phase of regeneration. Our findings emphasize the crucial importance of echinoderms to detect long-range expression conservation between vertebrates and classical invertebrate regeneration model systems.

Genome-wide identification of WUSHEL-related homeobox genes reveals their differential regulation during cold stress and in vitro organogenesis in Picrorhiza kurrooa Royle ex Benth.

Genome-wide identification of WUSHEL-related homeobox genes reveals their differential regulation during cold stress and in vitro organogenesis in Picrorhiza kurrooa Royle ex Benth.

Weiwei Decoction alleviates gastric intestinal metaplasia through the olfactomedin 4/nucleotide-binding oligomerization domain 1/caudal-type homeobox gene 2 signaling pathway.

Gastric intestinal metaplasia (IM) is a precancerous lesion that is associated with an elevated risk of gastric carcinogenesis. Weiwei Decoction (WWD) is a promising traditional Chinese herbal formula widely employed in clinical for treating IM. Previous studies suggested the potential involvement of the olfactomedin 4 (OLFM4)/nucleotide-binding oligomerization domain 1 (NOD1)/caudal-type homeobox gene 2 (CDX2) signaling pathway in IM regulation. To verify the regulation of the OLFM4/NOD1/CDX2 pathway in IM, specifically investigating WWD's effectiveness on IM through this pathway. Immunohistochemistry for OLFM4, NOD1, and CDX2 was conducted on tissue microarray. GES-1 cells treated with chenodeoxycholic acid were utilized as IM cell models. OLFM4 short hairpin RNA (shRNA), NOD1 shRNA, and OLFM4 pcDNA were transfected to clarify the pathway regulatory relationships. Protein interactions were validated by co-immunoprecipitation. To explore WWD's pharmacological actions, IM rat models were induced using N-methyl-N'-nitro-N-nitrosoguanidine followed by WWD gavage. Gastric cells were treated with WWD-medicated serum. Cytokines and chemokines content were assessed by enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction. The OLFM4/NOD1/CDX2 axis was a characteristic of IM. OLFM4 exhibited direct binding and subsequent down-regulation of NOD1, thereby sustaining the activation of CDX2 and promoting the progression of IM. WWD improved gastric mucosal histological lesions while suppressing intestinal markers KLF transcription factor 4, villin 1, and MUCIN 2 expression in IM rats. Regarding pharmacological actions, WWD suppressed OLFM4 and restored NOD1 expression, consequently reducing CDX2 at the mRNA and protein levels in IM rats. Parallel regulatory mechanisms were observed at the protein level in IM cells treated with WWD-medicated serum. Furthermore, WWD-medicated serum treatment strengthened OLFM4 and NOD1 interaction. In case of anti-inflammatory, WWD restrained interleukin (IL)-6, interferon-gamma, IL-17, macrophage chemoattractant protein-1, macrophage inflammatory protein 1 alpha content in IM rat serum. WWD-medicated serum inhibited tumor necrosis factor alpha, IL-6, IL-8 transcriptions in IM cells. The OLFM4/NOD1/CDX2 pathway is involved in the regulation of IM. WWD exerts its therapeutic efficacy on IM through the pathway, additionally attenuating the inflammatory response.

Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape

How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL’s histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.

Chromosome Xp22.3 deletion syndrome with X-linked ichthyosis, Kallmann syndrome, short stature, generalized epilepsy, hearing loss, attention deficit hyperactivity disorder, and intellectual disability – A rare report with review of literature

Chromosome Xp22.3 deletion syndrome is a very rare contiguous gene deletion syndrome with variable phenotype due to the deletion of genes from the distal short arm of the X chromosome (Xp), including the short-stature homeobox (SHOX), anosmin-1 (ANOS1), arylsulfatase (ARSL), neuroligin-4 (NLGN4), and steroid sulfatase (STS) genes. We have reviewed the available literature on the chromosome Xp22.3 deletion syndrome. A 10-year-old boy presented with global developmental delay, generalized epilepsy, decreased hearing, and hyperactivity. He had no significant family history. Examination revealed microcephaly, short stature, and dry and scaly skin lesions on the trunk. He had thick arched eyebrows, a depressed nasal bridge, a long philtrum, high arched palate, retrognathia, brachytelephalangy, brachymetatarsia, and mild scoliosis. Brainstem-evoked response audiometry testing revealed moderate hearing loss. Magnetic resonance imaging showed cerebellar tonsillar ectopia. Clinical exome sequencing revealed a likely pathogenic contiguous deletion (~8.10 Mb) spanning genomic location chrX:g.(_630898)_(8732037_)del encompassing ANOS1, ARSL, NLGN4X, SHOX, and STS genes. We have reviewed the available literature for reported associations of Chromosome Xp22.3 deletion syndrome and report a novel association of X-linked ichthyosis, Kallmann syndrome, global developmental delay, short stature, bilateral hearing loss, generalized epilepsy, attention deficit hyperactivity disorder, and intellectual disability.