Biology subjects

Sidhwani, P.

Publications and source records attributed to Sidhwani, P..

3 recordsLinked to original sources

bioRxiv2025

Histone H3 lysine methyltransferase activities control compartmentalization of human centromeres.

Centromeres are essential chromosomal regions that ensure accurate genome segregation during cell division. They are organized into epigenetically discrete compartments: a Centromere Protein A (CENP-A)-rich core for microtubule attachment and surrounding heterochromatic pericentromeres that promote cohesion. Despite their importance, the mechanisms that define, enforce and partition these chromatin domains remain poorly understood. To address this, we disrupted key H3K9 methyltransferases- SUV39H1, SUV39H2, and SETDB1- that establish heterochromatin in humans. We find that SETDB1 is required for H3K9 dimethylation at core centromeres, while SUV39H1/2 complete trimethylation. Unexpectedly, depleting all three enzymes results in aberrantly high H3K9me3, driving CENP-A expansion into pericentromeres. This promiscuous deposition is mediated by G9a/GLP methyltransferases, which selectively reestablish H3K9me3 within the centromere core. SETDB1, regardless of its enzymatic activity, blocks G9a/GLP-mediated heterochromatin deposition and CENP-A expansion, revealing a novel, catalytic-independent function in safeguarding centromeres. Overall, our work defines the molecular logic governing centromeric repression, and uncovers foundational principles of epigenetic compartmentalization.

genomics↗

bioRxiv2021

Complete genomic and epigenetic maps of human centromeres

Existing human genome assemblies have almost entirely excluded highly repetitive sequences within and near centromeres, limiting our understanding of their sequence, evolution, and essential role in chromosome segregation. Here, we present an extensive study of newly assembled peri/centromeric sequences representing 6.2% (189.9 Mb) of the first complete, telomere-to-telomere human genome assembly (T2T-CHM13). We discovered novel patterns of peri/centromeric repeat organization, variation, and evolution at both large and small length scales. We also found that inner kinetochore proteins tend to overlap the most recently duplicated subregions within centromeres. Finally, we compared chromosome X centromeres across a diverse panel of individuals and uncovered structural, epigenetic, and sequence variation at single-base resolution across these regions. In total, this work provides an unprecedented atlas of human centromeres to guide future studies of their complex and critical functions as well as their unique evolutionary dynamics. One-sentence summaryDeep characterization of fully assembled human centromeres reveals their architecture and fine-scale organization, variation, and evolution.

genomics↗

bioRxiv2019

Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract

Physical forces are important participants in the cellular dynamics that shape developing organs. During heart formation, for example, contractility and blood flow generate biomechanical cues that influence patterns of cell behavior. Here, we address the interplay between function and form during the assembly of the cardiac outflow tract (OFT), a crucial connection between the heart and vasculature that develops while circulation is underway. In zebrafish, we find that the OFT expands via accrual of both endocardial and myocardial cells. However, when cardiac function is disrupted, OFT endocardial growth ceases, accompanied by reduced proliferation and reduced addition of cells from adjacent vessels. The TGF{beta} receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct regulation of these essential cell behaviors. Together, our results suggest that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions.

developmental biology↗