Université de Strasbourg

Atish Mukherji

Biography - Atish Mukherji

Institute of Viral and Liver Disease (IVH), University of Strasbourg and Inserm

Atish Mukherji , USIAS Fellow 2020Atish Mukherji obtained his bachelor’s degree in biochemistry and master’s degree in biotechnology from the prestigious All India Institute of Medical Sciences in New Delhi. Subsequently, he obtained his PhD from the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi. In his doctoral work, he uncovered how the Hepatitis B Virus deregulates the cell cycle machinery to create a permissive environment for hepatocarcinogenesis.

Dr. Mukherji pursued his post-doctoral work in the laboratory of Professor Pierre Chambon at the Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, where he investigated how nuclear receptors transcriptionally regulate mammalian physiology. He co-discovered the existence of a novel mechanism of control of gene expression by the glucocorticoid receptor (Surjit et al., 2011, Cell). Building on this investigation and using spatiotemporal mutagenesis, he further demonstrated that the function of the multiple retinoic acid receptors is not redundant in vivo (Ganti et al., 2017, PNAS). He also discovered that the homeostasis in the intestinal epithelium is maintained by the circadian clock and microbiota cues transduced by the toll like receptors (Mukherji et al., 2013, Cell). Subsequently, he also discovered the intimate molecular connections between the circadian clock and systemic metabolism. These works established how abnormal feeding time perturbs the functioning of circadian clock and leads to the development of metabolic syndrome (Mukherji et al., 2015, PNAS), a situation which is often encountered in modern society due to ‘shift-work’ and jetlag.

In his present research, Dr. Mukherji aims to not only elucidate how the circadian clock machinery controls the functioning of human liver (Mukherji et al., 2019, J. Hepatology), but also to understand the molecular basis of chronic liver disease of different etiologies (Lupberger et al., 2019, Gastroenterology, and Juehling et al., 2020, Gut), with an overall goal to discover novel therapeutics for hepatocellular carcinoma.

Project - Investigating the role of the circadian clock and the 3-dimensional chromatin architecture in the development of hepatitis C virus (HCV)-induced liver disease

01/10/2020 - 30/09/2022

Each day, every living organism is subjected to changes in the light intensity generated by the Earth’s rotation around its own axis. To anticipate this geophysical variability, and to appropriately respond biochemically, species of many phyla, including mammals have evolved an approximate 24-hour endogenous timing mechanism known as the circadian clock (CC). The ‘clock’ is self-sustained, cell autonomous and is present in every cell type. At the core of the clock functioning resides the CC-oscillator, an exquisitely crafted transcriptional-translational feedback system. Remarkably, components of the CC-oscillator not only maintain daily rhythmicity of their own synthesis, but also generate temporal variability in the expression levels of numerous target genes through transcriptional, post-transcriptional and post-translational mechanisms. Thus, this ‘clock’-system ensures proper chronological coordination in the functioning of cells, tissues and organs, including that of the liver. Using mouse-genetics and genomic approaches, it has been demonstrated that the expression of nearly 20 % of genes in the liver are clock-controlled. Indeed, a variety of physiologically critical hepatic functions including glucose and lipid metabolism and detoxification of drugs are under regulation of the clock. The CC-machinery also commands expression of key genes involved in regulating immune functioning, cytokine signaling, autophagy and mitochondrial function. It is thus not a surprise that our modern lifestyle (jet lag, shift-work, energy-dense foods, etc.), which often disturbs CC functioning has recently emerged as a major contributor of different metabolic diseases such as obesity, diabetes, fatty liver, metabolic syndrome and cancer. Therefore, detailed understanding of the molecular basis of CC-control on gene expression is necessary to not only reveal the circadian basis of physiology and pathologies but also to develop novel therapeutics for metabolic and non-metabolic diseases whose therapeutic efficacy may be administration time-of-day dependent (chronomedicine).

Eukaryotic chromosomes are known to adopt complex hierarchical structures in the nucleus. The spatial folding of chromosomes - i.e. their three-dimensional (3D) organisation - in the nucleus profoundly affects DNA replication, transcription and repair. Hence, an understanding of the 3D-genomic architecture is essential for our understanding of the transcriptional basis of gene expression. Importantly, it has been suggested that CC-machinery could also control the 3D-chromatin organisation. Nevertheless, how 3D-genome architecture evolves and affects gene expression during the progression of complex multistep chronic human disease is barely known. Also unknown is the molecular relationship between the CC and chronic liver disease in humans.

The objective of this project is to study in detail the relationship between the hepatocytic CC and hepatitis C virus (HCV), which is a major contributor to hepatocellular carcinoma development throughout the world. Using hepatitis C virus infection of humanised mice livers and employing cutting edge genomic technologies such as Hi-C and its derivative promoter-capture-Hi-C, research will not only uncover the extent of clock control on human hepatocytes, but also the 3D-genomic architecture of human hepatocytes in different circadian phases. Furthermore, this project will uncover the molecular mechanisms through which the chromatin architecture is perturbed during the pathogenesis of a highly relevant chronic liver disease.

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