Biology subjects

Mohammed, J.

Publications and source records attributed to Mohammed, J..

11 recordsLinked to original sources

bioRxiv2026

Enhancer Tuning by Sequence-Specific Repressors

Enhancers integrate combinatorial inputs from sequence-specific transcription factors (TFs) and their activity must be calibrated to achieve precise spatiotemporal control of transcript dosage. Here we demonstrate that the sequence-specific repressors SNAI1 and SNAI2 (i.e. SNAIL and SLUG) quantitatively tune enhancer activity. In human neural crest cells, SNAI1/2 occupy a subset of active enhancers, where their depletion increases H3K27ac, chromatin accessibility, and enhancer regulatory potential. Changes in SNAI1/2 binding motifs contribute to enhancer divergence between human and chimpanzee, suggesting an evolutionary role for the repressor-mediated tuning. Single-molecule chromatin profiling using Deaminase-Assisted Fiber-seq (DAF-seq) reveals that individual enhancers toggle between an ensemble of open and nucleosome-dense chromatin states. While transcriptional activators increase the fraction of the open states, SNAI1/2 shift the equilibrium toward nucleosome-occupied states. This impedes binding of activator TFs, without fully repressing the enhancer. We propose that SNAI1/2 function as a molecular dimmer switch, modulating nucleosome dynamics to calibrate enhancer output.

molecular biology↗

bioRxiv2026

A peptide-based screen for cell death inhibitors identifies the cytoprotective compound CDL36

Small molecule inhibitors of cell death have wide-ranging potential applications, both as tool compounds in the laboratory and as clinical modulators of pathologic cell death. Previous screening efforts have identified candidate compounds targeting the pro-apoptotic, pore-forming BCL-2 family proteins BAX and BAK, but the complex interactions of these proteins at the mitochondrial outer membrane (with other proteins and the membrane itself) present challenges for compound screening. Although no inhibitors of BAX or BAK have advanced to clinical testing to date, candidate inhibitors have thus far been identified via screening of membrane-containing systems such as liposomes and isolated mitochondria. To address some of the challenges of chemical screening for apoptosis inhibitors, we conducted a small molecule screen utilizing BH3 profiling, a method that quantifies mitochondrial outer membrane permeabilization (MOMP) upon treatment with pro-apoptotic peptides derived from BCL-2 family proteins. Of over 40,000 compounds screened, we identified a series of compounds that prevent MOMP in response to pro-apoptotic peptides. The most potent of these, CDL36, binds to BAX and prevents MOMP at early timepoints. In longer term viability assays, the cytoprotective effect of CDL36 is most potent against death induced by doxorubicin, a widely used chemotherapeutic agent that causes dose-limiting cardiovascular toxicity. Our results elucidate the mechanism of action of new and existing cell death inhibitors, providing a foundation for further development of these inhibitors and potential insights into the mechanisms mediating doxorubicin toxicity in patients.

molecular biology↗

bioRxiv2025

The craniofacial shape of modern humans embodies genomic signatures of evolution, diversity, and clinical conditions

Human craniofacial morphology is a hallmark of our species diversity and evolutionary history, shaped by adaptation, introgression, and global dispersal. Cranial globularization and chin emergence are well-documented morphological transformations whose genetic basis remains poorly understood, whereas Neandertal introgression is primarily documented through genomic evidence. How these evolutionary phenomena relate to craniofacial variation in present-day humans remains largely unresolved. Here, we leverage 3D craniofacial data from over 50,000 UK Biobank participants and employ a multivariate, multiscale genome-wide association approach to define axes of variation aligned with inter-population allele frequency shifts, evolutionary processes, and clinical conditions. We identify continuous craniofacial trends within our cohort that mirror global patterns of genetic diversity, indicating that facial differences between human populations arise at the phenotypic axes already present within a single population. We further demonstrate that modern human-derived alleles underlie the origins of the human chin by reducing midfacial projection relative to other hominins and reveal the persistent effects of Neandertal introgression on craniofacial diversity today. We also model genetically informed endophenotypes for orofacial clefts, obstructive sleep apnoea, and myopia. These findings provide insights into our species evolutionary history and endophenotypes of clinical conditions and establish a framework for contextualizing craniofacial diversity into biologically meaningful axes of variation relevant to diverse scientific disciplines.

genetics↗

bioRxiv2025

A novel allele of Mitogen Activated Protein Kinase 6 is linked to disease resistance and constitutive immunity in rice.

Bacterial Blight (BB) is the most serious bacterial disease of rice. Usage of resistant cultivars has been a successful strategy in controlling BB. However, constant selection pressure causes the evolution of hypervirulent pathogenic strains that break down resistance, thus necessitating additional sources of resistance. An induced-mutant line derived from the elite rice cultivar Samba Mahsuri was identified to exhibit broad-spectrum resistance to BB. Using next-generation gene mapping approaches, we identified a genomic interval in chromosome 6 to be linked to BB resistance. Analysis of the SNPs in the locus and subsequent linkage analysis indicated that a missense SNP located in the second exon of the Mitogen-Activated Protein Kinase 6 (OsMAPK6) could be the causal mutation. A detailed examination of OsMAPK6 gene sequences in over 4000 rice genomes revealed that the mutant allele identified in this study is novel to rice germplasm. The candidate SNP causes the substitution of an invariant Serine residue with a Proline residue (S84P), thus likely affecting the protein function. Global transcriptome, metabolome, biochemical, and molecular analyses suggested that BB42 exhibit constitutive immunity. On the mechanistic front, the mutation seems to result in diminished brassinosteroid signaling in BB42. Taken together, we report a novel allele of a highly conserved MAPK gene and provide evidence for its possible association with constitutive immunity and disease resistance in rice.

plant biology↗

bioRxiv2023

Global control of cellular physiology by biomolecular condensates through modulation of electrochemical equilibria

Control of the electrochemical environment in living cells is typically attributed to ion channels. Here we show that the formation of biomolecular condensates can modulate the electrochemical environment in cells, which affects processes globally within the cell and interactions of the cell with its environment. Condensate formation results in the depletion or enrichment of certain ions, generating intracellular ion gradients. These gradients directly affect the electrochemical properties of a cell, including the cytoplasmic pH and hyperpolarization of the membrane potential. The modulation of the electrochemical equilibria between the intra- and extra-cellular environments by biomolecular condensates governs charge-dependent uptake of small molecules by cells, and thereby directly influences bacterial survival under antibiotic stress. The shift of the intracellular electrochemical equilibria by condensate formation also drives a global change of the gene expression profile. The control of the cytoplasmic environment by condensates is correlated with their volume fraction, which can be highly variable between cells due to the stochastic nature of gene expression at the single cell level. Thus, condensate formation can amplify cell-cell variability of the environmental effects induced by the shift of cellular electrochemical equilibria. Our work reveals new biochemical functions of condensates, which extend beyond the biomolecules driving and participating in condensate formation, and uncovers a new role of biomolecular condensates in cellular regulation.

cell biology↗

bioRxiv2023

The Rapidly Evolving X-linked miR-506 Family Finetunes Spermatogenesis to Enhance Sperm Competition

Despite rapid evolution across eutherian mammals, the X-linked miR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (Slitrk2 and Fmr1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked miR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernable defects, but simultaneous ablation of five clusters containing nineteen members of the miR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked miR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the miR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis. Significance StatementThe X-linked miR-506 family has rapidly evolved in mammals, but their physiological significance remains elusive. Given their abundant and preferential expression in the testis and sperm, these X-linked miRNAs likely play a functional role in spermatogenesis and/or early embryonic development. However, the deletion of either individual miRNA genes or all of the five miRNA clusters encoding 38 mature miRNAs did not cause major fertility defects in mice. When these mutant males were subjected to conditions resembling polyandrous mating, the mutant sperm were much less competitive than the wild-type sperm, rendering the mutant males "functionally sub-fertile". Our data suggest that the miR-506 family of miRNAs regulates sperm competition and the reproductive fitness of the male.

developmental biology↗

bioRxiv2022

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, rs6740960 SNP is sufficient to confer a large difference in acetylation of its cognate enhancer preferentially in chondrocytes. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

developmental biology↗

bioRxiv2021

A genome-wide genetic screen uncovers novel determinants of human pigmentation

The skin color is one of the most diverse human traits and is determined by the quantity, type and distribution of melanin. Here, we leverage light scattering properties of melanin to conduct a genome-wide CRISPR-Cas9 screen for novel regulators of melanogenesis. We identify functionally diverse genes converging on melanosome biogenesis, endosomal transport and transcriptional/posttranscriptional gene regulation, most of which represent novel associations with pigmentation. A survey of transcriptomes from diversely pigmented individuals reveals that the majority of genes discovered in our screen are upregulated in dark skin melanocytes, in agreement with their melanin-promoting function and potential contribution to skin color variation. This association is further buttressed by the significant skin color heritability enrichment in the vicinity of these genes. Taken together, our study presents a novel approach to assay pigmentation and uncovers a plethora of melanogenesis regulators, with broad implications for human variation, cell biology and medicine. One Sentence SummaryGenetic screen uncovers genes involved in human melanogenesis, many of which are differentially expressed in individuals of diverse skin color.

cell biology↗

bioRxiv2021

Doxorubicin Induces Senescence in Intestinal Epithelial Cells

Doxorubicin treatment induces DNA damage and apoptosis in rapidly dividing cell types like intestinal epithelial cells. This has been demonstrated both in vivo and in vitro. In certain cell types some cells do not undergo DNA damage-induced apoptosis in response to doxorubicin but instead become senescent. Induction of senescence in these cells can lead to dysfunction and chronic inflammation, which can lead to more damage. We questioned whether a single dose of doxorubicin would be able to induce apoptosis and senescence in intestinal epithelial cells in vitro. For these studies, we exposed IEC-6 small intestinal epithelial cells to doxorubicin to evaluate whether senescence is induced in a relatively homogeneous population of intestinal epithelial cells. Although some cells underwent apoptosis, those that did not showed traits of senescence. Our studies showed that doxorubicin treatment increased cell size and increased expression of senescence-associated {beta}-galactosidase. Concomitantly, we observed increased mRNA expression of several genes associated with a senescence-associated secretory phenotype including IL-6, Ptges, Faim2, and Cdkn1a and decreased expression of Sirt1. We also observed release of HMGB1, a cellular alarmin, from treated cells. Together, these data suggest that doxorubicin induces senescence in intestinal epithelial cells. Furthermore, our data indicate that cellular responses to a DNA damaging agent, such as doxorubicin, can differ within a population of cells suggesting differing levels of sensitivity within a relatively homogenous cell population. Further studies are needed to delineate the mechanisms that determine whether a cell moves down an apoptotic or senescent pathway following DNA damage.

cell biology↗

bioRxiv2020

Insights into the genetic architecture of the human face

The human face is complex and multipartite, and characterization of its genetic architecture remains intriguingly challenging. Applying GWAS to multivariate shape phenotypes, we identified 203 genomic regions associated with normal-range facial variation, 117 of which are novel. The associated regions are enriched for both genes relevant to craniofacial and limb morphogenesis and enhancer activity in cranial neural crest cells and craniofacial tissues. Genetic variants grouped by their contribution to similar aspects of facial variation show high within-group correlation of enhancer activity, and four SNP pairs display evidence of epistasis, indicating potentially coordinated actions of variants within the same cell types or tissues. In sum, our analyses provide new insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.

genetics↗

bioRxiv2017

Deep experimental profiling of microRNA diversity, deployment, and evolution across the Drosophila genus

Comparative genomic analyses of microRNAs (miRNAs) have yielded myriad insights into their biogenesis and regulatory activity. While miRNAs have been deeply annotated in a small cohort of model organisms, evolutionary assessments of miRNA flux are clouded by the functional uncertainty of orthologs in related species, and insufficient data regarding the extent of species-specific miRNAs. We address this by generating a comparative small RNA (sRNA) catalog of unprecedented breadth and depth across the Drosophila genus, extending our extant deep analyses of D. melanogaster with sRNA data from multiple tissues of 11 other fly species. Aggregate analysis of several billion sRNA reads permits curation of accurate and holistic compendia of miRNAs across this genus, providing abundant opportunities to identify species- and clade-specific variation in miRNA identity, abundance, and processing. Amongst well-conserved miRNAs, we observe unexpected cases of clade-specific variation in 5' end precision, occasional antisense loci, and some putatively non-canonical loci. We also employ strict criteria to identify a massive set (649) of novel, evolutionarily-restricted miRNAs. Amongst the bulk collection of species-restricted miRNAs, two notable subpopulations of rapidly-evolving miRNAs are splicing-derived mirtrons and testis-restricted, clustered (TRC) canonical miRNAs. We quantify rates of miRNA birth and death using our annotation and a phylogenetic model for estimating rates of miRNA turnover in the presence of annotation uncertainty. We show striking differences in birth and death rates across miRNA classes defined by biogenesis pathway, genomic clustering, and tissue restriction, and even identify variation heterogeneity amongst Drosophila clades. In particular, distinct molecular rationales underlie the distinct evolutionary behavior of different miRNA classes. We broaden observations made from D. melanogaster as Drosophilid-wide principles for opposing evolutionary viewpoints for miRNA maintenance. Mirtrons are associated with a high rate of 3' untemplated addition, a mechanism that impedes their biogenesis, whereas TRC miRNAs appear to evolve under positive selection. Altogether, these data reveal miRNA diversity amongst Drosophila species and permit future discoveries in understanding their emergence and evolution.

genomics↗