Biology subjects

Cohen, B.

Publications and source records attributed to Cohen, B..

10 recordsLinked to original sources

bioRxiv2026

Evolution of a genome-architecture-encoded gene regulation system in trypanosomatids

Transcriptional regulation of protein-coding genes is a hallmark of eukaryotic gene expression. Yet, a group of parasitic protists, trypanosomatids, appear to lack this capability. Here, we analyzed genomic, nascent transcriptomic, RNA polymerase occupancy and gene organization data to reconstruct the evolutionary origin and biological consequences of their unusual regulatory strategy. Across 59 Discoba protists, we show stepwise evolutionary erosion of conventional transcription regulation components in trypanosomatida lineage, including gene consolidation into polycistronic transcription units (PTUs), shortening of intra-PTU non-coding regions, and depletion of transcription factors and their enriched DNA-binding motifs. This transition was associated with near-constitutive expression of most genes, indicating broad loss of conditional gene expression. However, trypanosomatids retain some differential regulation at the PTU level, with >70% PTUs featuring significantly different nascent transcription than their neighbors or resident chromosomes. Moreover, gene expression is not uniform within PTUs: nascent transcription, translation efficiency, and protein abundance progressively decline with distance from the transcription start site. Consistent with this architecture-encoded regulatory logic, co-complex subunits and co-pathway enzymes preferentially occupy adjacent positions within PTUs despite each PTUs overall functional heterogeneity. These findings reveal an evolutionary shift from gene-specific transcriptional regulation toward a regime where genome architecture becomes a regulator of gene expression.

evolutionary biology↗

bioRxiv2026

An information content principle explains regulatory patterns of gene expression across human tissues

Gene expression patterns range from broadly expressed housekeeping genes to highly tissue-specific ones. Notably, many genes exhibit intermediate specificity, characterized by elevated expression in some tissues while low or absent in others. Understanding how regulatory demands scale with tissue specificity offers a valuable opportunity to uncover fundamental principles of genome regulation. By analyzing cis-regulatory element (CRE) counts across human genes with varying tissue specificity, we observed a nonlinear pattern: genes with intermediate specificity harbor the highest CRE count, suggesting distinct regulatory strategies across the expression spectrum. Motivated by this observation, we used the Minimum Description Length (MDL) principle from information theory, together with a maximum parsimony approach from phylogenetics, to quantify regulatory demands across tissues. Our analysis revealed that MDL-based regulatory demand scales consistently with diverse regulatory features, including CRE count, transcription-factor and microRNA targeting, and gene structure. To test whether this scaling changes across the expression spectrum, we partitioned genes by expression breadth. Two patterns emerged: features scaling with MDL in selectively expressed genes tend to act as on/off switches, whereas those in ubiquitous genes serve as fine-tuning knobs. Evolutionary analysis revealed that these regulatory patterns vary with gene age, with alignment between MDL and CRE counts peaking in intermediate-aged genes. Collectively, these results establish MDL combined with maximum parsimony as a powerful framework linking regulatory architecture, expression specificity, and evolutionary age, offering novel insights into the organizational principles underlying genome regulation.

genomics↗

bioRxiv2023

Longitudinal hair cortisol in bipolar disorder and a mechanism based on HPA dynamics

Bipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on a timescale of months to years. BD patients characteristically exhibit elevated levels of the hormone cortisol. Persistently elevated cortisol can also cause mood episodes in a substantial fraction of the general population. Although BD is a dynamic disease that is related to cortisol, longitudinal cortisol dynamics in BD have rarely been studied. Here we use hair to measure past cortisol where each cm of hair corresponds to a month of growth. Cortisol was measured in 12 cm hair samples from people with BD (n=26) and controls (n=59), corresponding to one year of cortisol data. We found that hair cortisol exhibited a frequency spectrum with enhanced year-scale fluctuations whose amplitude was about 4-fold higher on average in BD compared to controls. Cortisol in the proximal 2 cm hair segment correlated with mood scales that report on mood in the past two months. In line with the notion that cortisol correlates with mood, we find that the mean frequency spectrum of depression (n=266) and mania (n=273) scores from a large longitudinal study of BD is similar to the hair cortisol spectrum from the present cohort. Taken together, these results suggest a mechanism for BD as the intersection of two neuropsychological traits: cortisol-induced mood episodes (CIM) and high emotional reactivity (ER). High ER causes fluctuations in which cortisol is elevated for months, as shown by a mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis that regulates cortisol. In individuals with CIM, the magnitude of these persistent cortisol fluctuations can be high enough to trigger mood episodes. Thus, this study combines longitudinal cortisol measurements and mathematical modeling to provide a potential mechanistic link between the timescales of cortisol and moods in BD.

systems biology↗

bioRxiv2021

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

cell biology↗

bioRxiv2021

Going Beyond the Point Neuron: Active Dendrites and Sparse Representations for Continual Learning

Biological neurons integrate their inputs on dendrites using a diverse range of non-linear functions. However the majority of artificial neural networks (ANNs) ignore biological neurons structural complexity and instead use simplified point neurons. Can dendritic properties add value to ANNs? In this paper we investigate this question in the context of continual learning, an area where ANNs suffer from catastrophic forgetting (i.e., ANNs are unable to learn new information without erasing what they previously learned). We propose that dendritic properties can help neurons learn context-specific patterns and invoke highly sparse context-specific subnetworks. Within a continual learning scenario, these task-specific subnetworks interfere minimally with each other and, as a result, the network remembers previous tasks significantly better than standard ANNs. We then show that by combining dendritic networks with Synaptic Intelligence (a biologically motivated method for complex weights) we can achieve significant resilience to catastrophic forgetting, more than either technique can achieve on its own. Our neuron model is directly inspired by the biophysics of sustained depolarization following dendritic NMDA spikes. Our research sheds light on how biological properties of neurons can be used to solve scenarios that are typically impossible for traditional ANNs to solve.

neuroscience↗

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗

bioRxiv2021

p53 mutations exhibit sex specific gain-of-function activity in gliomagenesis

The tumor suppressor TP53 is the most frequently mutated gene in cancer. Most TP53 mutations are missense mutations in the DNA-binding domain, which in addition to loss of canonical p53 activity, frequently confer gain-of-function (GOF) aberrant transcriptional activity through mutant p53 localization to non-canonical genes. GOF phenotypes differ by mutation and cell identity and are reported to include increased proliferation, migration, metabolic reprogramming, and therapy resistance. We found that several recurring p53 mutations exhibit a sex-bias in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53R172H, p53Y202C, and p53Y217C revealed sex differences in each mutations ability to transform primary mouse astrocytes. p53R172H exhibited a far greater ability to transform female astrocytes than males, p53Y202C transformed both male and female astrocytes with a small male bias, and p53Y217C only exhibited GOF transformation effects in male astrocytes. These phenotypic differences reflect an interaction between sex and GOF mutation to drive unique gene expression patterns in cancer pathways. We found that mutant p53 exhibits sex and mutation specific aberrant genomic localization to the transcriptional start sites of upregulated genes, whose promoter regions were enriched for different sets of transcription factor DNA-binding motifs. Together, our data establish a novel paradigm for sex specific mutant p53 GOF activity in GBM with implications for all cancer.

cancer biology↗

bioRxiv2021

Mitochondria serve as axonal shuttle for Cox7c mRNA through mechanism that involves its mitochondrial targeting signal

Localized protein synthesis plays a key role in spatiotemporal regulation of the cellular proteome. Neurons, which extend axons over long distances, heavily depend on this process. However, the mechanisms by which axonal mRNAs are transported to protein target sites are not fully understood. Here, we describe a novel role for mitochondria in shuttling a nuclear encoded mRNA along axons. Fractionation analysis and smFISH revealed that the mRNA encoding Cox7c protein is preferentially associated with mitochondria from a neuronal cell line and from primary motor neuron axons. Live cell imaging of MS2-tagged Cox7c or Cryab control mRNA in primary motor neurons further confirmed the preferential colocalization of Cox7c mRNA with mitochondria. More importantly, Cox7c demonstrated substantial cotransport with mitochondria along axons. Intriguingly, the coding region, rather than the 3UTR, was found to be the key domain for the cotransport. Furthermore, we show that puromycin treatment as well as hindering the synthesis of the mitochondrial targeting signal (MTS) reduced the colocalization. Overall, our results reveal a novel mRNA transport mode which exploits mitochondria as a shuttle and translation of the MTS as a recognition feature. Thus, mitochondria may play a role in spatial regulation of the axonal transcriptome and self-sustain their own proteome at distant neuronal sites.

cell biology↗

bioRxiv2019

BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, downregulation of bach2a hinders blood-vessel formation and impairs lymphatic sprouting in a vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1-overexpression enhances intratumoral blood-vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.

developmental biology↗

bioRxiv2019

A single TRPV1 amino acid controls species sensitivity to capsaicin

Chili peppers produce capsaicin, the principle chemical that accounts for the culinary sensations of heat. Capsaicin activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) on sensory neurons to alter the membrane potential to induce pain. While structural studies have identified residues important for the binding of capsaicin to rat TRPV1, there is still no clear understanding of differential capsaicin sensitivity of TRPV1 between birds and mammals. To determine the residues dictating relative capsaicin sensitivity among species, we have used intracellular Ca2+ imaging to characterize chimeras composed of capsaicin-sensitive rat TRPV1 (rTRPV1) and capsaicin-insensitive chicken TRPV1 (cTRPV1) with a series of capsaicinoids. We find that chimeras containing rat E570-V686 swapped into chicken receptors displays capsaicin sensitivity, and that a single amino acid substitution in the S4-S5 helix, changing the alanine at position 578 in the chick receptor to a glutamate, is sufficient to endow micromolar capsaicin sensitivity. Moreover, introduction of lysine, glutamine or proline at A578 also install capsaicin sensitivity in cTRPV1. Comparing the derivatives Cap-EA and Cap-EMA with capsaicin, these two compounds with the hydrophilic vanilloid-like moiety affect the protein-ligand interaction. The ability of 10 M Cap-EA to activate cTRPV1-A578E and the differential response of mutants to the analogs suggests that chick A578 may participate in vanilloid binding, as does the corresponding rTRPV1 site. The hydrophilic vanilloid agonist zingerone 500 M failed to activate any A578 mutants that retained capsaicin sensitivity, suggesting that the vanilloid group alone is not sufficient for receptor activation. Replacing the rTRPV1-E570 residue with K, Q shows a similar tendency to maintain the receptor capsaicin sensitivity. Our study demonstrates a subtle modification on different species TRPV1 globally alter their capsaicin response.

molecular biology↗