Cells retain tlieir identity in part by inheriting gene expression profiles of their predecessors. Patterns of transcription that survive cell division are thought to be established and maintained partly through covalent modifications of histones and DNA, and do not involve changes in the DNA sequence itself. Emerging evidence increasingly implicates this epigenetic mode of inheritance in a myriad of developmental processes as well as a cause of or a significant contributor to human disease. My research strives to further our understanding of epigenetic mechanisms through the study of X-chromosome Inactivation (XCI). XCI is an instrument of dosage compensation in mammals that results in the transraiptlonal silencing of genes on one of the two X-chromosomes in eariy female embryos. Once enacted in individual cells, XCI is stably transmitted such that all descendant ceils maintain silencing of that X-chromosome. Since an entire chromosome is inactivated and tfierefore easily detected, XCI is a model system to investigate transcriptional memory mechanisms. Importantly, the memory mechanisms that operate during XCI also apply broadly to gene regulation and are being found to be important in cell fate decisions during embryogenesis and in stem cell biology as well as during disease progression. We have recently identified a novel protein enriched on the inactive X-chromosome (Xi), This protein is predicted to be a novel putative methyltransferase. The Xi is a target of two known MTases (Ezh2 and Pr- Set7), which operate on the Xi to propagate transcriptional memory by catalyzing the methylation of histones either on their own or In a complex with other proteins. We will therefore deteimine if the novel protein mediates cellular memory through histone methylation, using established biochemical assays to detect histone methylation on core histones as well as on nudeosome substrates. We also aim to Identify proteins that with which It interacts. We will also generate mice bearing a conditional-null mutation in the gene to analyze its requirement in XCI.

Public Health Relevance

Emerglr^ evidence increasingly implicates the mis-reguIatlon of the epigenetic machinery as a cause of or a significant contributor to human disease. The identification and delineation of novel epigenetic factors and their function will provide insight into the mechanisms that are either bypassed or co-opted in human disorders, including various cancers.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Transition Award (R00)
Project #
5R00HD055333-04
Application #
7944096
Study Section
Special Emphasis Panel (NSS)
Program Officer
Oster-Granite, Mary Lou
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$246,509
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hinten, Michael; Maclary, Emily; Gayen, Srimonta et al. (2016) Visualizing Long Noncoding RNAs on Chromatin. Methods Mol Biol 1402:147-164
Kang, Jinsuk; Lienhard, Matthias; Pastor, William A et al. (2015) Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis. Proc Natl Acad Sci U S A 112:E4236-45
Gayen, Srimonta; Maclary, Emily; Buttigieg, Emily et al. (2015) A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation. Cell Rep 11:1251-65
Maclary, Emily; Buttigieg, Emily; Hinten, Michael et al. (2014) Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation. Nat Commun 5:4209
Kang, Jinsuk; Kalantry, Sundeep; Rao, Anjana (2013) PGC7, H3K9me2 and Tet3: regulators of DNA methylation in zygotes. Cell Res 23:6-9
Jiao, Baowei; Ma, Hong; Shokhirev, Maxim N et al. (2012) Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells. Cell 149:630-41
Kalantry, Sundeep (2011) Recent advances in X-chromosome inactivation. J Cell Physiol 226:1714-8
Williams, Lucy H; Kalantry, Sundeep; Starmer, Joshua et al. (2011) Transcription precedes loss of Xist coating and depletion of H3K27me3 during X-chromosome reprogramming in the mouse inner cell mass. Development 138:2049-57