Welcome to the Laboratory of

Gene Expression and Metabolism

@KSBS, IIT-Delhi

During development, controlled patterns of gene expression regulate multiple aspects of cell proliferation and differentiation. My laboratory research is focused on understanding how cells transition from proliferation to differentiation, and from quiescence to re-entry into the cell cycle. Our goal is to discern the regulatory events underlying these transitions since it is fundamental to understanding how tissues/organs are formed, maintained and repaired, and altered during disease, particularly cancer.

Such cell state transitions are spatio-temporally regulated by gene expression programs driven by specific combinations of transcription factors, cofactors and chromatin regulators. In our laboratory, we study an ubiquitously expressed epigenetic coregulator of transcription called as HCF-1, a herpes simplex virus host-cell factor. HCF-1 is encoded by the X-linked HCFC1 and Hcfc1 genes in humans and mice, respectively. HCF-1 binds to the transcriptional start sites of many genes and physically links sequence-specific DNA-binding transcription factors with chromatin-modifying enzymes, such as mixed-lineage leukemia (MLL) and Set1 histone H3 lysine 4 (H3K4) methyltransferases. It is required for cell proliferation during both embryogenesis and liver regeneration. Recently, we have shown that the hepatocyte-specific Hcfc1 knockout (KO) mice rapidly recapitulate features of non-alcoholic fatty liver disease (NAFLD) progression to terminal non-alcoholic hepatosteatosis (NASH) characterized by hyperlipidemia, mitochondrial defects, increased inflammation and cell death, fibrosis, progenitor cell activation, and metabolic dysfunction including defective gluconeogenesis. The severe phenotype associated with loss of HCF-1 is likely due to the multiple roles it plays in liver physiology via the stabilization of PGC1a protein and regulation of gene transcription particularly of those genes involved in a wide variety of mitochondrion-associated functions. After long being known for its role in cell proliferation, these recent studies suggest that HCF-1 plays critical role in the functions of differentiated tissues through a multiplicity of mechanisms yet to be fully elucidated.

We propose to now investigate how HCF-1 modulates dynamics of gene expression during cell state transitions and metabolic alterations with diverse and integrated molecular, genetic, biochemical, and genomic approaches. For this, we will make use of both mammalian cell culture and animal models in which HCF-1 expression can be altered. Our specific goals are:

1. To elucidate the role of HCF-1 in the regulation of cell differentiation.

2. To understand the role of HCF-1 in the metabolic functions of quiescent hepatocytes, particularly in lipid metabolism.

3. To understand the role of HCF-1 in the proliferative functions of hepatocytes during liver regeneration.

4. Uncovering the regulatory mechanisms that maintain metabolic homeostasis during liver regeneration and upon injury (NAFLD).