The fields of chromatin biology and epigenetics have experienced explosive growth in the last several years. Much of this growth has been enabled by technical advances in genome sequencing and proteomics, and buoyed by genetic links to human health and disease. The epigenome is an additional layer of chemical information that acts on top of the genome and informs gene expression. The complex array of posttranslational modifications (PTMs) to histone proteins, which act as molecular spools for wrapping DNA, is a major epigenetic mechanism for controlling transcriptional programs. These enzyme-catalyzed histone modifications (e.g. (de)acetylation and (de)methylation) result in a unique set of chemical 'marks'that regulate chromatin function, largely through unknown mechanisms. We and others have proposed that combinatorial posttranslational modifications (PTMs) give rise to a histone 'code'or 'language', which is interpreted by enzyme complexes to mediate transcriptional responses. New information suggests that 'reader'domains, which are protein:protein interaction modules, act within enzyme complexes to function as molecular interpreters of this combinatorial PTM code. However, direct molecular evidence is scarce. Thus, there is tremendous need to understand the molecular mechanisms of this essential process. Here, we will employ a number of innovative approaches to investigate the existence of a functional histone code and how this epigenetic language is read to control gene expression. The impact of this work toward human health is substantial: There is mounting genetic evidence that mutations in chromatin 'reader'domains are directly linked to human disease, and there are recent reports that 'reader'proteins can be targeted for drug development. The results of our mechanistic work will directly inform drug development.
Three aims are proposed: 1.) To elucidate the binding mechanisms of tandem-domain chromatin readers, 2.) To define the PTM state of nucleosomes recognized by multivalent chromatin reader proteins, and 3.) To determine how chromatin enzymes utilize multivalent protein modules to read the PTM code written in nucleosomes.

Public Health Relevance

The epigenome is an additional layer of chemical information that acts on top of the genome and informs which genes are expressed and which are genes are silenced. Much like the genetic code, the complex array of these chemical 'marks'is proposed to act as an epigenetic code or language. Unfortunately, researchers currently lack the ability to decipher this molecular language. Here, we will employ innovative approaches to investigate how this epigenetic language is read to control gene expression. The impact of this work on human health is substantial: There is mounting genetic evidence that mutations in molecular 'code-readers'are directly linked to human disease. The results of this mechanistic work will directly inform drug development. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37GM059785-15
Application #
8579128
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Gerratana, Barbara
Project Start
1999-08-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$307,566
Indirect Cost
$97,566
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Su, Zhangli; Boersma, Melissa D; Lee, Jin-Hee et al. (2014) ChIP-less analysis of chromatin states. Epigenetics Chromatin 7:7
Gough, Sheryl M; Lee, Fan; Yang, Fan et al. (2014) NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer Discov 4:564-77