Saha Institute of Nuclear Physics
Saha Institute of Nuclear Physics
Chromatin Dynamics Lab
Prof Chandrima Das
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Applications for a 1-year Research Associate position are invited from eligible candidates for the successful implementation of a DST SwarnaJayanti project under the mentorship of Prof. Chandrima Das, Associate Professor F, in the Biophysics & Structural Genomics Division of Saha Institute of Nuclear Physics. For details visit the PDF.
Our Research
Our research group is part of the Biophysics & Structural Genomics Division at Saha Institute of Nuclear Physics, Kolkata. We are interested to understand the fundamental mechanisms of altered epigenetic regulation in human diseases. In this context, we are working on a specific class of proteins called chromatin “readers/effectors”, which are known to impact the epigenetic mechanisms in normal conditions as well as diseased states. Our research helps to shed light on the crucial roles of these epigenetic regulators in maintaining chromatin landscape and plasticity. Among the different functions of chromatin readers, we are especially keen to know more about the following topics summarized below.
Breast cancer is one of the major causesof mortality in females. The heterogeneity of the disease is a therapeutic challenge. Through early diagnosis breast cancer has been challenged with conventional therapies, which include chemotherapy, radiation therapy, hormonal therapy and surgery. Complexities arises with a particular sub-type of the disease, which is Triple-Negative Breast cancer (TNBC), as this particular sub-type is the most aggressive and therapeutically non-responsive form of the disease, with potential chances of relapse. In this context, our laboratory is working on a few important chromatin reader proteins - Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7), SUMO E3 Ligase Chromobox 4 (CBX4) and Zinc Finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8 (ZMYND8). Our work on UBR7 led to its establishent as a novel histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis in TNBC throughmodulating Wnt/β-Catenin signaling pathway (Nat Commun., 2019). We have found CBX4 to be a SUMO E3 ligase of hTERT (catalytic subunit of human telomerase enzyme), positively regulating its activity and consequently promoting breast cancer migration and invasion (Biochem J., 2020). ZMYND8 has been shown to harbor conventional CHD4-independent functions in regulating gene expression through its modified histone binding ability (J Biol Chem., 2016). Further, ZMYND8 has been shown to suppress tumorigenicity through independent molecular mechanisms: (i) Positive regulation of epithelial gene expression programs (Biochem J., 2017), (ii) Negative regulation of tumor promoting geneexpression programs (Cell Death Dis., 2020), (iii) Induction of cellular differentiationprograms (J Biosci., 2020). Interestingly, the role of ZMYND8 in modulating retinoid-based therapy (as an all trans retinoic acid-responsive transcription factor), opens up new avenues to combat tumor growth through an epigenetic perspective (Biochim Biophys Acta Gene Regul Mech., 2017).
Role of epigenetic readers in tumorigenicity:
Fig 1a: UBR7 ubiquitinates H2BK120 (marked by green triangle) and along with elongating RNA Polymerase complex activates transcription programs to maintain the epithelial phenotype of cells and acts as a tumor suppressor. UBR7 has emerged as a potent suppressor of breast tumorigenesis.
Fig 1b: Multiple modes of regulation of cellular transcription programs by chromatin reader ZMYND8 to suppress breast tumorigenesis. It can repress a poised epigenetic program (A) or differentially regulate gene expression programs leading to either activation (through its dual histone binding property, in association with RNA Polymerase complex) (B) or repression (through association with NuRD complex) (C) in association with different protein complexes and act as a potent tumor suppressor.
The prevalence of global health problems like type 1/2 diabetes, obesity and other metabolic disorders has garnered a lot ofattention, and increasing studies indicate an epigenetic regulation can influence metabolic disease progression. Our laboratory has adapted a multi-pronged strategy to understand the interdependence of epigenetic regulation and metabolic homeostasis. We have established the role of PIP5K, an enzyme involved in phosphoinositide signaling, in ribosomal RNA gene silencing through a unique epigenetic mechanism (J Biol Chem., 2015). We have recently shown that PHD finger harbouring protein Transcription Factor 19 (TCF19) is a novel glucose and insulin responsive transcription factor that modulates histone post-translational modifications to regulate glucose homeostasis in hepatocytes (J Biol Chem., 2017).Further, our study has also elucidated that TCF19 acts as a pro-oncogene and its functional PHD finger is critical in cell proliferation (Biochemistry, 2019). Recent ongoing research from our laboratory establishes the role of TCF19 in mitochondrial energy metabolism and stress adaptation in conjunction with the tumor suppressor protein p53. Further, functional interplay between TCF19 and TCF7L2, a crucial effector of the Wnt pathway, in maintaining the metabolic milieu during Endoplasmic Reticulum stress is also being actively pursued in our laboratory.
Role of epigenetic readers in metabolic disorders
Fig 2: TCF19 can repress transcription programs through interaction with H3K4Me3 modification in association with NuRD (A) or activate the same in association with p53-p300 complex (B) and is implicated in maintaining cell cycle and metabolic homeostasis which go awry in metabolic disorders.
Hepatitis B virus (HBV) remains a major health problem worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC); although the outcome of the infection varies widely among infected individuals. The anti-viral drugs that are in use have various limitations and constant efforts are being made to develop more cost-effective and potential drugs. Interestingly, new strategies are being exploited by which host immune-suppressive transcription factors are targeted to evade viral infection. Research from our laboratory has recently uncovered a mechanism by which HBV can evade host immune-response by hijacking host protein Speckled 110 (Sp110) and therefore proposed the latter to be a novel target for antiviral therapy (J Biol Chem., 2017). Further, our future laboratory research is also aiming towards metabolic rewiring of the HBV infected host cells by the chromatin readers to strategically combat viral infection.
Role of epigenetic readers in pathogenic infection
Fig 3: Sp110 gets hijacked by viral cofactor HBx during Hepatitis B virus infection and differentially regulates cellular transcription programs (either activates, A or represses, B) through association with different protein complexes during infection for favourable viral proliferation.
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