Martin J Walsh, PhD

The capacity to reprogram gene expression programs determine the fate of cells to self renew, differentiate or terminate. The transcription of genetic information from DNA is the fundamental process that regulates gene expression and requires elaborate and complex signals necessary to overcome the normally repressive state of chromatin. Our laboratory has focused on understanding the mechanisms that regulate gene expression through processes that recognize and establish epigenetic character in chromatin necessary to facilitate or repress gene transcription. Much of our recent work has been in close collaboration with Ming-Ming Zhou to adopt innovative approaches that will understand the molecular, structural and biochemical basis for epigenetic control of gene expression. Recently, our studies solved the molecular structure and the biochemical function of the SWIRM domain, a phylogenetically conserved structure common in many chromatin-associated proteins. Much of our ongoing effort has been to combine structure -guided analysis that will utilize chemistry-based experimental designs to determine the molecular and cellular function of chromatin proteins in vivo in a more effective manner. Future studies plan to exploit the physical structure of proteins that interact with DNA, RNA and modified histones and to use chemical probes to assess their biochemical and cellular function in a native cellular environment. Ongoing studies also exploit the use of chromatin immunoprecipitation sequencing (ChIP-Seq) and high -density sequencing maps to determine the global impact on cellular chromatin. Below is a brief summary of ongoing projects in the laboratory.

Regulation of chromatin structure by human CUTL1 transcription factor-
Our focus has been directed on two fundamental transcription factors that play key roles in both oncogenic transformation and during development called the CCAAT displacement protein/cut homologue (CUTL1) and zinc finger protein 217 (ZNF217/zfp217). CUTL1 in man and cux in mouse are essential for development and self -renewal in various tissue compartments in metazoan vertebrates. CUTL1 is also a key determinant in promoting tumor cell migration and metastasis. We have previously shown that CUTL1 can mediate the acetylation and methylation of nucleosomal histones through the differential recruitment and of histone acetyltransferase (HAT), histone deacetylase (HDAC), and histone lysine metyltransferase (HMT) activities. We have also demonstrated that CUTL1 is a substrate of many of these enzymes that determine the function of CUTL1. Although, transcription factors have the ability to bind DNA they typically lack the capacity to navigate chromatin structure necessary to access cognate DNA sequences. Many transcriptional co-regulators provide the function to recognize and bind post-translational -modified nucleosomal histone. When tethered to co-regulators, transcription factors attain the ability to associate with highly ordered chromatin structure and impose their regulatory function. Our ongoing studies are investigating the role novel nuclear co-regulators and their conserved protein domains that can "read" the histone code by binding modified histone residues that mark functional domains within chromatin. Identification and analysis by ChIP-Seq of transcriptional co-regulators for CUTL1 and the histone marks they impose will help us determine the "visual scope" and native context for CUTL1 occupation within the human genome.