A5003288507- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- Animal Genetics and Reproduction
- Genetics and Neurodevelopmental Disorders
- Cancer-related molecular mechanisms research
- Down syndrome and intellectual disability research
- Pluripotent Stem Cells Research
- RNA Research and Splicing
- Renal and related cancers
- Congenital heart defects research
- RNA modifications and cancer
- Genetic Syndromes and Imprinting
- Mitochondrial Function and Pathology
- Genomic variations and chromosomal abnormalities
- Genomics and Rare Diseases
- Cancer-related gene regulation
- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
University of Connecticut
2020-2025
UConn Health
2016-2025
Massachusetts General Hospital
2009-2018
Howard Hughes Medical Institute
2009-2018
Harvard University
2011-2018
Princeton University
2008
X chromosome inactivation (XCI) achieves dosage balance in mammals by repressing one of two chromosomes females. During XCI, the long noncoding Xist RNA and Polycomb proteins spread along inactive (Xi) to initiate chromosome-wide silencing. Although is known commence at X-inactivation center (Xic), how it propagates remains unknown. Here, we examine allele-specific binding repressive complex 2 (PRC2) chromatin composition during XCI generate a profile Xi Xa (active X) nucleosome-resolution....
Abstract A hallmark of chromosome organization is the partition into transcriptionally active and repressed B compartments, topologically associating domains (TADs). Both structures were regarded to be absent from inactive mouse X chromosome, but re-established with transcriptional reactivation chromatin opening during X-reactivation. Here, we combine a tailor-made iPSC reprogramming system high-resolution Hi-C produce time course combining gene reactivation, topology Contrary previous...
Abstract The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome organized. Xi shows weakened topologically associated domains instead organized into megadomains superloops directed by noncoding loci, Dxz4 Firre . Their functional significance presently unclear, though one study suggests that they permit genes to escape silencing. Here, we find do not precede Xist expression or gene Deleting disrupts sharp...
Abstract In mammals, several classes of monoallelic genes have been identified, including those subject to X-chromosome inactivation (XCI), genomic imprinting, and random expression (RMAE). However, the extent which these epigenetic phenomena are influenced by underlying genetic variation is unknown. Here we perform a systematic classification allelic imbalance in mouse hybrids derived from reciprocal crosses divergent strains. We observe that deviation balanced biallelic common, occurring...
Schizosaccharomyces pombe Pfh1p is an essential member of the Pif family 5'-3' DNA helicases. The two Saccharomyces cerevisiae homologs, Pif1p and Rrm3p, function in nuclear replication, telomere length regulation, mitochondrial genome integrity. We demonstrate here existence multiple isoforms that localized to either nuclei or mitochondria. catalytic activity was both cellular compartments. absence resulted G(2) arrest accumulation damage foci, a finding suggestive role replication....
Abstract In mammals, X-chromosome inactivation (XCI) equalizes X-linked gene expression between XY males and XX females is controlled by a specialized region known as the X-inactivation center (Xic). The Xic harbors two chromatin interaction domains, one centered around noncoding Xist other antisense Tsix counterpart. Previous work demonstrated existence of transitional zone domains. Here, we investigate discover conserved element, RS14, that presents strong binding site for Ctcf protein....
Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which remain amenable to intervention after development is unknown. To address this question a model of DS neurogenesis, we derived trisomy (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls mosaic fibroblasts equipped one chr21 copy with an inducible XIST transgene. Monoallelic silencing by near-complete...
Female human pluripotent stem cells (hPSCs) routinely undergo inactive X (Xi) erosion. This progressive loss of key repressive features follows the XIST expression, long non-coding RNA driving inactivation, and causes reactivation silenced genes across eroding (Xe). To date, sporadic nature erosion has obscured its scale, dynamics, transition events. address this problem, we perform an integrated analysis DNA methylation (DNAme), chromatin accessibility, gene expression hundreds hPSC...
Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the Y chromosome in males and escape X inactivation (XCI) females. Inferred to reflect pair dosage sensitivity, monosomy is a leading cause of miscarriage humans with near full penetrance. This phenotype shared many other mammals but not mouse, which offers sophisticated genetic tools generate chromosomal aneuploidy also tolerates its developmental impact. To address this critical gap, we generated X-monosomic...
Recent efforts in mapping spatial genome organization have revealed three evocative and conserved structural features of the inactive X female mammals. First, chromosomal conformation reveals a loss topologically-associated domains (TADs) present on active X. Second, macrosatellite DXZ4 emerges as singular boundary that suppresses physical interactions between two large TAD-depleted "megadomains". Third, reaches across several megabases to form "superloops" with other X-linked tandem...
Gene expression is controlled by coordinated action of many epigenetic mechanisms including covalent histone modifications. Although numerous recurrent patterns colocalized modifications have been associated with specific gene states, interrelationships between individual are largely unknown. Here, we analyze quantitative relationships marks during embryonic stem cell (ESC) differentiation and find that, for autosomal genes, these densities follow bimodal patterns. Analysis repressive...
In mammals, monoallelic gene expression can result from X-chromosome inactivation, genomic imprinting, and random (RMAE). Epigenetic regulation of RMAE is not fully understood. Here we analyze allelic imbalance in chromatin state autosomal genes using ChIP-seq a clonal cell line. We identify approximately 3.7% that show significant differences between states two alleles. Allelic represented among several functional categories including histones, modifiers, multiple early developmental...
SUMMARY Modeling the developmental etiology of viable human aneuploidy can be challenging in rodents due to syntenic boundaries, or primate-specific biology. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which contrast remain unaffected 39,X-mice. To learn how may impact early embryonic we turned 45,X isogenic euploid induced pluripotent stem cells (hiPSCs) from male female mosaic donors. Because neural...
ABSTRACT The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome organized. Xi shows weakened topologically associated domains instead organized into megadomains superloops directed by noncoding loci, Dxz4 Firre . Their functional significance presently unclear, though one study suggests that they permit genes to escape silencing. Here, we find do not precede Xist expression or gene Deleting disrupts megadomain...
Summary A hallmark of chromosome organization is the partition into transcriptionally active and repressed B compartments topologically associating domains (TADs). Both structures were regarded absent from inactive X chromosome, but to be re-established with transcriptional reactivation chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC-reprogramming system high-resolution Hi-C produce first time-course combining gene reactivation, topology Contrary previous...
SUMMARY Female human pluripotent stem cells (hPSCs) are prone to undergoing X chromosome erosion (XCE), a progressive loss of key epigenetic features on the inactive that initiates with repression XIST , long non-coding RNA required for inactivation. As result, previously silenced genes eroding (Xe) reactivate, some which thought provide selective advantages. To-date, sporadic and nature XCE has largely obscured its scale, dynamics, transition events. To address this knowledge gap, we...
ABSTRACT/SUMMARY Excess gene dosage from human chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental as well acute phenotypes in terminal cell types. Which remain amenable to intervention after development is unknown. To address this question a model of DS neurogenesis, we generated trisomy (T21) induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls mosaic fibroblasts, and integrated an inducible XIST transgene on one chr21 copy. Monoallelic...