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Biology subjects

Borad, P.

Publications and source records attributed to Borad, P..

3 recordsLinked to original sources

Notch/Hairless Pathway Modulation of sog Transcriptional Bursting in Prelude to Gastrulation

Transcriptional regulation, orchestrated by the interplay between transcription factors (TFs) and enhancers, governs gene expression dynamics crucial for cellular processes. While gross, qualitative fluctuations in transcription factor-dependent gene expression patterning have a long history of characterization, the roles of these factors in the nuclei retaining expression in the presence or absence of these factors are now observable using modern techniques. Our study investigates the impact of Suppressor of Hairless (Su(H)), a broadly expressed transcription factor, on enhancer-driven transcriptional modulation using Drosophila early embryos as a model system. Building upon previous findings, we employ super-resolution microscopy to dissect Su(H)s influence on sog Distal (sogD) enhancer activity specifically in nuclei with preserved sogD-driven expression in the absence of Su(H) binding. We demonstrate that Su(H) occupancy perturbations alter expression levels and bursting dynamics. Notably, Su(H) absence during embryonic development exhibits region-specific effects, inhibiting expression dorsally and enhancing expression ventrally, implying a nuanced role in enhancer regulation. Our findings shed light on the intricate mechanisms that govern transcriptional dynamics and suggest a patterning role for Notch/Hairless signaling in sog expression during the transition to gastrulation.

developmental biology↗

Cell-specific occupancy dynamics between the pioneer-like factor Opa/ZIC and Ocelliles/OTX regulate early head development in embryos

During development, embryonic patterning systems direct a set of initially uncommitted pluripotent cells to differentiate into a variety of cell types and tissues. A core network of transcription factors, such as Zelda/POU5F1, Odd-paired (Opa)/ZIC and Ocelliless (Oc)/OTX, are conserved across animals. While Opa is essential for a second wave of zygotic activation after Zelda, it is unclear whether Opa drives head cell specification past gastrulation onset, in the Drosophila embryo. Our hypothesis is that Opa and Oc are interacting with distinct cis-regulatory regions for shaping cell fates in the embryonic head. Using super-resolution microscopy and epigenomic meta-analysis of single cell RNAseq datasets we find that opas and ocs overlapping expression domains are dynamic in the head region, with both factors being simultaneously transcribed at the blastula stage. However, analysis of single-embryo RNAseq data reveals a subgroup of Opa-bound genes to be Opa-independent in the cellularized embryo. Interrogation of these genes against Oc ChIPseq combined with in situ data, suggests that Opa is competing with Oc for the regulation of a subgroup of genes later in gastrulation. Specifically, we find that Oc binds to late, head-specific enhancers independently and activates them in a head-specific wave of zygotic transcription, suggesting distinct roles for Oc in the blastula and gastrula stages.

developmental biology↗

Cycling hypoxia selects for constitutive HIF stabilization

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF- stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF- stabilization becomes constitutive even under normoxia, a condition known as pseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF- and its client proteins based on fitness. The model shows that facultative regulation of HIF- always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF- regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF- regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.

cancer biology↗