The goal of this project is to elucidate the functions of mammalian H1 linker histones in gene regulation and development. Along with the four core histones (H2A, H2B, H3 and H4) that assemble DNA into nucleosomes, the H1 linker histones play key roles in organizing the structure of the chromatin fiber. Mammals express multiple, non-allelic, evolutionarily conserved H1 variants or subtypes that differ in their primary sequences and in their expression during development. These subtypes, each encoded by a single copy gene, provide additional levels of regulation of chromatin function. Although there has been substantial progress in understanding the roles of core histones in chromatin structure and function, current knowledge about H1's is quite limited. We propose to help fill this gap by elucidating the functions, mechanisms of action and subtype-specific activities of mammalian H1 linker histones in gene regulation and development. To investigate the functions of mammalian H1's in vivo, we have generated and characterized mouse embryonic stem cells and mice in which one or several H1 genes have been inactivated by gene targeting. We also have studied the functions of H1's with chromatin reconstituted in vitro. These studies have revealed unexpected roles and modes of action for H1 in helping to control DNA and histone methylation. The work also has uncovered important functional differences among the H1 subtypes. To gain a deeper understanding of the mechanisms by which H1 participates in gene regulation and development, we propose to pursue the following specific aims: (1) To elucidate the functions of H1 linker histones in regulating core histone post-translational modifications; (2) To understand the mechanisms by which certain H1 subtypes help control DNA methylation; (3) To determine the roles played by H1's in red blood cell development. The successful completion of the proposed work will lead to new insights into mechanisms of gene regulation and a deeper understanding of the functional significance of the diversity present in the mammalian H1 family. It will also begin to define the roles of this major constituent of chromatin in the well-defined process of red blood cell development.

Public Health Relevance

The goal of this project is to understand the functions of H1 linker histones, a major family of proteins involved in regulating the structure and activity of mammalian chromosomes. H1's are essential for normal embryonic/fetal development, including the production of red blood cells. Thus, perturbations in the synthesis or functions of H1's can contribute to numerous human diseases including anemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM116143-19
Application #
9490379
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
1998-04-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
19
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Fyodorov, Dmitry V; Zhou, Bing-Rui; Skoultchi, Arthur I et al. (2018) Emerging roles of linker histones in regulating chromatin structure and function. Nat Rev Mol Cell Biol 19:192-206
Kokavec, Juraj; Zikmund, Tomas; Savvulidi, Filipp et al. (2017) The ISWI ATPase Smarca5 (Snf2h) Is Required for Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells. Stem Cells 35:1614-1623
Andreyeva, Evgeniya N; Bernardo, Travis J; Kolesnikova, Tatyana D et al. (2017) Regulatory functions and chromatin loading dynamics of linker histone H1 during endoreplication in Drosophila. Genes Dev 31:603-616
Kavi, Harsh; Emelyanov, Alexander V; Fyodorov, Dmitry V et al. (2016) Independent Biological and Biochemical Functions for Individual Structural Domains of Drosophila Linker Histone H1. J Biol Chem 291:15143-55
He, Shuying; Limi, Saima; McGreal, Rebecca S et al. (2016) Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation. Development 143:1937-47
Xu, Na; Lu, Xingwu; Kavi, Harsh et al. (2016) BEN domain protein Elba2 can functionally substitute for linker histone H1 in Drosophila in vivo. Sci Rep 6:34354
Geeven, Geert; Zhu, Yun; Kim, Byung Ju et al. (2015) Local compartment changes and regulatory landscape alterations in histone H1-depleted cells. Genome Biol 16:289