Molecular Dissection Of Epigenetic And Epitranscriptomic Pathways In Gene Regulation For The Maintenance Of The Embryonic Stem Cells State
Molecular dissection of epigenetic and epitranscriptomic pathways in gene regulation for the maintenance of the embryonic stem cells state Varun Pandey, Pratibha Tripathi, Partha Pratim Das Epigenetics and Gene Regulation Laboratory,Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Clayton VIC 3800 Australia Genetic information flows from DNA to RNA (transcription) and RNA to protein (translation) – referred to as the ‘central dogma’ of molecular biology. ‘Epigenetic’ modification takes place on DNA and histones without changing the DNA sequences to control transcriptional output (DNA to RNA). While ‘epitranscriptomic/ RNA epigenetic’ modification happens in RNAs (at the post-transcriptional level) without altering the RNA sequences to control RNA turnover and translation. Hence, RNA modifications add a new paradigm to the central dogma. To date, more than 150 RNA modifications have been identified in different classes of RNAs in various organisms; only a few of them are commonly occurring and emerging fields of study in gene regulation. Although epigenetic and epitranscriptomic modifications act at different layers of gene regulation programs, recently, a handful of studies revealed the ‘crosstalk’ between these two pathways in controlling gene expression. However, the underlying mechanisms are not yet fully understood and remain a critical area of research interest in the gene regulation field. N6-methyladenosine (m6A) RNA methylation is the most abundant, and reversible internal RNA modification discovered in eukaryotic mRNAs, and non-coding RNAs (lncRNAs) play crucial roles in splicing, export, decay/stability and translation that ultimately control various biological processes. The deposition of m6A is catalyzed by the m6A-methyltransferases – METTL3, METTL14 (m6A-writers). Conversely, m6A deposition can be removed by m6A-demethylases – FTO and ALKBH (m6A-erasers). In addition, a group of m6A-binding proteins (m6A-readers) – such as YTHDF1-3, YTHDC1-2, IGF2BP1-3 and HNRNPs — have been identified that recognise m6A in mRNAs and govern the fate of their targeted mRNAs. Nevertheless, current knowledge regarding the molecular and biological function of m6A-readers is incomplete and controversial. Hence, we have expanded the search to identify new m6A-readers in murine embryonic stem cells (mESCs), which identified UPF1 as a novel m6A-reader. My research focuses on investigating the molecular functions of UPF1 and its roles in maintaining the mESCs state. In addition, I found a physical interaction between LSD1/KDM1A (histone demethylase that removes H3K4me1,2 marks from histone tail) and YTHDF2 (m6A-reader) in mESCs. This emerged as a new avenue to study the crosstalk between epigenetic and epitranscriptomic pathways and their functions in gene regulation for the ESC maintenance that is currently underway. Altogether, these studies will delineate – the tasks of new m6A-reader protein in the m6A pathway; also establish further mechanistic details in connecting epigenetic and epitranscriptomic pathways for gene regulation – to maintain the ESC state, impacting regenerative biology.