Our laboratory is dedicated to studying the epigenetic mechanisms in cancer. We are specifically focused on understanding the functional role of arginine citrullination in transcriptional plasticity in cancer.
Transcription regulation by RNA polymerase II is a fundamental process that is guided by tissue-specific transcription factors. These factors play a critical role in proliferation, cell identity, and function, and their dysregulation contributes to oncogenesis and drug resistance. Understanding the molecular mechanisms that regulate the recruitment of protein complexes to the transcription machinery is therefore essential for deciphering the fundamental processes underlying these pathological conditions.
Post-translational modifications of chromatin, including arginine citrullination, are crucial components of gene regulation mechanisms. Arginine citrullination is the conversion of arginine to the non-coded amino acid citrulline, catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). We are deciphering the molecular mechanisms by which PADIs-mediated citrullination coordinates with transcriptional events at multiple levels and dictates transcriptional plasticity and immune regulation in cancer.
Given our expertise in the field of arginine citrullination and transcription regulation, we are intrigued to elucidate how arginine citrullination implicates the distinct stages of transcriptional events in cancer. Using advanced multidisciplinary approaches inclusive of single-cell omics, microscopy, proteomics, and the CRISPR-Cas9 method along with structural knowledge, we aim to gain a comprehensive understanding of the molecular mechanisms underlying this process. In combination, we are using functional approaches to translate this fundamental knowledge to provide better therapeutic strategies for cancer patients.
Priyanka Sharma (Inserm)
Villanueva-Cañas et al. (2023) Evolutionary insights reveal a new role of PADI2 in transcription elongation. bioRvix
Beato & Sharma. (2020) Peptidyl arginine deiminase 2 (PADI2)-mediated arginine citrullination modulates transcription in cancer. Int J Mol Sci
Sharma et al. (2018) Arginine citrullination at the C-terminal domain controls RNA Polymerase II transcription. Mol Cell
Sharma et al. (2012) Citrullination of histone H3 interferes with HP1-mediated transcriptional repression. PLOS Genet
Surface representation of peptidyl arginine deiminase 2 with the consensus interface with the P-TEFb (positive transcription elongation factor b) complex derived from AlphaFold-Multimer and docking structural models highlighted in red and Leucine 162 in blue.
We are grateful to our collaborators, including:
• Prof. Juan Valcàrcel Juarez, Centre for Genomic Regulation (CRG), Barcelona, Spain
• Prof. Xavier Salvatella, Institute for Biomedical Research (IRB), Barcelona, Spain
• Dr. Daan Noordermeer, Institute for Integrative Biology of the Cell (I2BC), Université Paris Saclay, Paris, France
• Dr. Narcis Fernandez-Fuentes, Aberystwyth University, United Kingdom
• Prof. Baldomero Oliva, Department of Medicine and Life Sciences, University Pompeu Fabra, Barcelona, Spain