Covalent modifications of histones, such as acetylation, methylation, phosphorylation, and ubiquitylation, are essential regulators of chromatin structure and function. Defects in the regulation of these modifications have causal roles in numerous developmental disorders and diseases. However, the mechanisms that target histone-modifying enzymes to specific genomic locations and regulate their enzymatic activities are not well understood. Our long-term goal is to understand how diverse histone modification activities are coordinated to initiate and maintain different epigenetic states. Heterochromatin preferentially assembles at repetitive DNA elements. It is critical for setting up gene expression patterns during development and maintaining genome integrity by rendering repetitive structures recombinationally inert. It is also crucial for functional organization of vital chromosomal structures such as centromeres and telomeres, ensuring the accurate segregation of genetic material during mitosis and meiosis. Heterochromatin formation requires the concerted actions of diverse histone modifying enzymes as well as the RNA interference (RNAi) machinery. Paradoxically, transcription of the underlying repetitive DNA elements is also required for proper heterochromatin assembly, although heterochromatin generally represses transcription. These transcripts not only serve as substrates for RNAi to produce small interfering RNAs (siRNAs), but also as a platform for the recruitment of histone-modifying enzymes through siRNA-containing effector complexes. Histone modifications in turn stabilize the binding of the RNAi machinery to heterochromatin. As a result, processing of transcripts by RNAi and recruitment of histone modifying activities are tightly coupled, making it difficult to identify the initial signas that target repetitive regions for heterochromatin assembly. We have recently discovered that loss of a number of factors allows cells to bypass the requirement of the RNAi machinery for heterochromatin assembly. Our studies of the one class of these factors, the Mst2 histone acetyltransferase complex, revealed that reducing RNA polymerase recruitment to heterochromatin during DNA replication is essential for the inheritance of the heterochromatic state through generations. The goal of this proposal is to further understand how loss of diverse activities could bypass the RNAi requirement for heterochromatin assembly. These analyses will provide molecular mechanisms of how heterochromatin-promoting activities are regulated to control the initiation, spreading, and maintenance of heterochromatin domains.

Public Health Relevance

Public health relevance statement Misregulation of heterochromatin assembly leads developmental disorders and contributing significantly to the progression of cancers. Our proposed studies using a genetically tractable model organism will provide important mechanistic insights into heterochromatin assembly and will contribute to the development of new avenues to treat diseases associated with deregulation of heterochromatin.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM085145-06A1
Application #
8694896
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
2008-07-01
Project End
2018-02-28
Budget Start
2014-05-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Graduate Schools
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027
Shan, Chun-Min; Wang, Jiyong; Xu, Ke et al. (2016) A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading. Elife 5:
Wang, Jiyong; Cohen, Allison L; Letian, Anudari et al. (2016) The proper connection between shelterin components is required for telomeric heterochromatin assembly. Genes Dev 30:827-39
Wang, Jiyong; Jia, Sharon T; Jia, Songtao (2016) New Insights into the Regulation of Heterochromatin. Trends Genet 32:284-94
Wang, Jiyong; Reddy, Bharat D; Jia, Songtao (2015) Rapid epigenetic adaptation to uncontrolled heterochromatin spreading. Elife 4:
Wang, Jiyong; Tadeo, Xavier; Hou, Haitong et al. (2014) Tls1 regulates splicing of shelterin components to control telomeric heterochromatin assembly and telomere length. Nucleic Acids Res 42:11419-32
Cohen, Allison L; Jia, Songtao (2014) Noncoding RNAs and the borders of heterochromatin. Wiley Interdiscip Rev RNA 5:835-47
Wang, Jiyong; Lawry, Stephanie T; Cohen, Allison L et al. (2014) Chromosome boundary elements and regulation of heterochromatin spreading. Cell Mol Life Sci 71:4841-52
Kallgren, Scott P; Andrews, Stuart; Tadeo, Xavier et al. (2014) The proper splicing of RNAi factors is critical for pericentric heterochromatin assembly in fission yeast. PLoS Genet 10:e1004334
Hou, Haitong; Kallgren, Scott P; Jia, Songtao (2013) Csi1 illuminates the mechanism and function of Rabl configuration. Nucleus 4:176-81
Wang, Jiyong; Tadeo, Xavier; Hou, Haitong et al. (2013) Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries. Genes Dev 27:1886-902

Showing the most recent 10 out of 17 publications