Epigenetic Regulation: Covalent histone marks, DNA methylation and CHD family chromatin remodelers

Mammals have hundreds of structurally and physiologically distinct cell types like liver, heart etc. All cell types contain identical genes; however their cellular identity, memory and functions are determined by expression of only a set of genes. Histone proteins pack DNA/genes into nucleosome. Covalent chemical tags like ‘methyl, acetyl and phosphate’ on histones and ‘methyl’ mark on DNA are part of ‘epigenetic information’ that play a pivotal role in determining what set of genes should be expressed in a given cell type. Thus, these epigenetic marks create meaningful variations in the template of the eukaryotic genome (nucleosome) and can transform one genome into hundreds of ‘epigenomes and/ or transcriptomes’ that have relevance in transcription, DNA repair and recombination. We aim to understand how these chemical tags on histones and DNA are established (written), removed (erased) and/ or recognized (read) by the enzymatic machineries and protein complexes. Our objectives are gaining structural and mechanistic insights into the functional relevance of histone covalent modifications, DNA methylation and ATP dependent chromatin remodelers in epigenetic regulation.

HMG proteins from fungal and protozoa pathogens: Role in topological modulation of DNA structure and regulation of DNA repair proteins activity

High mobility group (HMG) proteins, are non-histone chromatin architectural proteins, bind different DNA structures and chromatin, induce conformational changes in the chromatin and topological changes in DNA that facilitate the replication, transcription, recombination and repair of both nuclear and mitochondrial DNA. HMG proteins also participate in packaging of mitochondrial DNA (mtDNA) into highly organized structures called mitochondrial nucleoids. They bind DNA repair proteins and enzymes, and regulate (stimulate or inhabit) their activities. The mechanisms related to HMGs’ functioning are important because they play key roles in maintenance of genome integrity, and are associated with cancer development, inflammation and autoimmune disorders and fungal pathogenesis.

Long term goal is to use selected HMGs as model to address the following important questions.

• How they recognize non-canonical DNAs?
• How they induce the topological changes in DNA relevance to DNA packing, repair and recombination?
• How they affect the DNA repair factors activities?

Our lab’s aim is to use a multi-pronged approaches complementing structural (X-ray crystallography), biochemical and genetical techniques that each feed into one another to develop a molecular model of macromolecules described above.