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.
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. !
| Zhang, Xue-Song; Li, Jackie; Krautkramer, Kimberly A et al. (2018) Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. Elife 7: |
| Qian, Shuiming; Lv, Xinchen; Scheid, Ray N et al. (2018) Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL. Nat Commun 9:2425 |
| Kuznetsov, Vyacheslav I; Haws, Spencer A; Fox, Catherine A et al. (2018) General method for rapid purification of native chromatin fragments. J Biol Chem 293:12271-12282 |
| Yang, Zhenlin; Qian, Shuiming; Scheid, Ray N et al. (2018) EBS is a bivalent histone reader that regulates floral phase transition in Arabidopsis. Nat Genet 50:1247-1253 |
| Krautkramer, Kimberly A; Rey, Federico E; Denu, John M (2017) Chemical signaling between gut microbiota and host chromatin: What is your gut really saying? J Biol Chem 292:8582-8593 |
| Sanders, Dean; Qian, Shuiming; Fieweger, Rachael et al. (2017) Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy. Plant Physiol 173:2243-2252 |
| Krautkramer, Kimberly A; Dhillon, Rashpal S; Denu, John M et al. (2017) Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin. Transl Res 189:30-50 |
| Su, Zhangli; Denu, John M (2016) Reading the Combinatorial Histone Language. ACS Chem Biol 11:564-74 |
| Su, Zhangli; Wang, Fengbin; Lee, Jin-Hee et al. (2016) Reader domain specificity and lysine demethylase-4 family function. Nat Commun 7:13387 |
| Morris, Brett A; Burkel, Brian; Ponik, Suzanne M et al. (2016) Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells. EBioMedicine 13:146-156 |
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