Pragya Sidhwani

All Publications

• Epigenetic inheritance and boundary maintenance at human centromeres. Current opinion in structural biology Sidhwani, P., Straight, A. F. 2023; 82: 102694

  Abstract

  Centromeres are chromosomal regions that provide the foundation for microtubule attachment during chromosome segregation. Centromeres are epigenetically defined by nucleosomes containing the histone H3 variant centromere protein A (CENP-A) and, in many organisms, are surrounded by transcriptionally repressed pericentromeric chromatin marked by trimethylation of histone H3 lysine 9 (H3K9me3). Pericentromeric regions facilitate sister chromatid cohesion during mitosis, thereby supporting centromere function. Heterochromatin has a known propensity to spread into adjacent euchromatic domains unless it is properly bounded. Heterochromatin spreading into the centromere can disrupt kinetochore function, perturbing chromosome segregation and genome stability. In the fission yeast Schizosaccharomyces pombe, tRNA genes provide barriers to heterochromatin spread at the centromere, the absence of which results in abnormal meiotic chromosome segregation. How heterochromatin-centromere boundaries are established in humans is not understood. We propose models for stable epigenetic inheritance of centromeric domains in humans and discuss advances that will enable the discovery of novel regulators of this process.

  View details for DOI 10.1016/j.sbi.2023.102694

  View details for PubMedID 37657353

• Complete genomic and epigenetic maps of human centromeres. Science (New York, N.Y.) Altemose, N., Logsdon, G. A., Bzikadze, A. V., Sidhwani, P., Langley, S. A., Caldas, G. V., Hoyt, S. J., Uralsky, L., Ryabov, F. D., Shew, C. J., Sauria, M. E., Borchers, M., Gershman, A., Mikheenko, A., Shepelev, V. A., Dvorkina, T., Kunyavskaya, O., Vollger, M. R., Rhie, A., McCartney, A. M., Asri, M., Lorig-Roach, R., Shafin, K., Lucas, J. K., Aganezov, S., Olson, D., de Lima, L. G., Potapova, T., Hartley, G. A., Haukness, M., Kerpedjiev, P., Gusev, F., Tigyi, K., Brooks, S., Young, A., Nurk, S., Koren, S., Salama, S. R., Paten, B., Rogaev, E. I., Streets, A., Karpen, G. H., Dernburg, A. F., Sullivan, B. A., Straight, A. F., Wheeler, T. J., Gerton, J. L., Eichler, E. E., Phillippy, A. M., Timp, W., Dennis, M. Y., O'Neill, R. J., Zook, J. M., Schatz, M. C., Pevzner, P. A., Diekhans, M., Langley, C. H., Alexandrov, I. A., Miga, K. H. 2022; 376 (6588): eabl4178

  Abstract

  Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions.

  View details for DOI 10.1126/science.abl4178

  View details for PubMedID 35357911

• Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract. Development (Cambridge, England) Sidhwani, P., Leerberg, D. M., Boezio, G. L., Capasso, T. L., Yang, H., Chi, N. C., Roman, B. L., Stainier, D. Y., Yelon, D. 2020; 147 (12)

  Abstract

  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 under way. 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 flow-responsive TGFβ receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct modes of function-dependent regulation for each of these essential cell behaviors. Together, our results indicate that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions. Moreover, these morphogenetic mechanisms provide new perspectives regarding the potential causes of cardiac birth defects.

  View details for DOI 10.1242/dev.185900

  View details for PubMedID 32439760

  View details for PubMedCentralID PMC7328156

• Fluid forces shape the embryonic heart: Insights from zebrafish. Current topics in developmental biology Sidhwani, P., Yelon, D. 2019; 132: 395-416

  Abstract

  Heart formation involves a complex series of tissue rearrangements, during which regions of the developing organ expand, bend, converge, and protrude in order to create the specific shapes of important cardiac components. Much of this morphogenesis takes place while cardiac function is underway, with blood flowing through the rapidly contracting chambers. Fluid forces are therefore likely to influence the regulation of cardiac morphogenesis, but it is not yet clear how these biomechanical cues direct specific cellular behaviors. In recent years, the optical accessibility and genetic amenability of zebrafish embryos have facilitated unique opportunities to integrate the analysis of flow parameters with the molecular and cellular dynamics underlying cardiogenesis. Consequently, we are making progress toward a comprehensive view of the biomechanical regulation of cardiac chamber emergence, atrioventricular canal differentiation, and ventricular trabeculation. In this review, we highlight a series of studies in zebrafish that have provided new insight into how cardiac function can shape cardiac morphology, with a particular focus on how hemodynamics can impact cardiac cell behavior. Over the long-term, this knowledge will undoubtedly guide our consideration of the potential causes of congenital heart disease.

  View details for DOI 10.1016/bs.ctdb.2018.12.009

  View details for PubMedID 30797515

  View details for PubMedCentralID PMC6394863

• FGF signaling enforces cardiac chamber identity in the developing ventricle. Development (Cambridge, England) Pradhan, A., Zeng, X. I., Sidhwani, P., Marques, S. R., George, V., Targoff, K. L., Chi, N. C., Yelon, D. 2017; 144 (7): 1328-1338

  Abstract

  Atrial and ventricular cardiac chambers behave as distinct subunits with unique morphological, electrophysiological and contractile properties. Despite the importance of chamber-specific features, chamber fate assignments remain relatively plastic, even after differentiation is underway. In zebrafish, Nkx transcription factors are essential for the maintenance of ventricular characteristics, but the signaling pathways that operate upstream of Nkx factors in this context are not well understood. Here, we show that FGF signaling plays an essential part in enforcing ventricular identity. Loss of FGF signaling results in a gradual accumulation of atrial cells, a corresponding loss of ventricular cells, and the appearance of ectopic atrial gene expression within the ventricle. These phenotypes reflect important roles for FGF signaling in promoting ventricular traits, both in early-differentiating cells that form the initial ventricle and in late-differentiating cells that append to its arterial pole. Moreover, we find that FGF signaling functions upstream of Nkx genes to inhibit ectopic atrial gene expression. Together, our data suggest a model in which sustained FGF signaling acts to suppress cardiomyocyte plasticity and to preserve the integrity of the ventricular chamber.

  View details for DOI 10.1242/dev.143719

  View details for PubMedID 28232600

  View details for PubMedCentralID PMC5399623

• KefB inhibits phagosomal acidification but its role is unrelated to M. tuberculosis survival in host. Scientific reports Khare, G., Reddy, P. V., Sidhwani, P., Tyagi, A. K. 2013; 3: 3527

  Abstract

  kefB is annotated as a potassium/proton antiporter in M. tuberculosis. There have been divergent reports on the involvement of KefB in phagosomal maturation in M. bovis BCG and no investigation has been carried out on its role in M. tuberculosis, the pathogenic species responsible for causing tuberculosis. This study was taken up to ascertain the involvement of KefB in the growth of M. tuberculosis and its role in phagosomal maturation and survival of the pathogen in guinea pigs. Our findings show that kefB mutant of M. tuberculosis (MtbΔkefB) was impaired i) for growth in high concentrations of potassium and ii) in arresting phagosomal acidification. However, the disruption of kefB had no adverse effect on the survival of M. tuberculosis in macrophages as well as in guinea pigs suggesting that the role of KefB in phagosomal acidification is unrelated to the survival of the pathogen in the host.

  View details for DOI 10.1038/srep03527

  View details for PubMedID 24346161

  View details for PubMedCentralID PMC3866608