Epigenetics and Cell Differentiation
Each of the cells in our body contains the same genetic information, passed down since fusion of the maternal and paternal gametes took place. However, each cell is capable of differentiating to form the different cell types, including neurons, lymphocytes and muscle cells, which make up the multitude of tissues in the human body. We study the mechanisms, known as epigenetics, responsible for this cellular flexibility. Epigenetic information is present in the cell’s nucleus, organising the DNA as chromatin. It regulates gene expression during all the major events in life (embryonic development, cell proliferation and differentiation).
DNA is organized by dedicated proteins, forming a highly dynamic structure, called chromatin. Its essential element is the nucleosome, which is comprised of four different core histones (H2A H2B H3 and H4), diverse histone variants, and linker histones H1. Several levels of organization coexist, from the famous “beads on a string structure” to the metaphasic chromosome.
The following movie nicely illustrates the organization levels of chromatin:
From wehi.tv at the Walter and Eliza Hall Institute.
We are particularly interested in gamete formation, particularly male gametes. Each sperm cell transmits not only the father’s genes, but also a very specific epigenome. Indeed, the sperm nucleus is reorganised to make it very compact. This involves a complete reprogramming step. During this reorganisation, the main protein components of chromatin, histones, are replaced by protamines, placement of which is a key element in determining fertility. The field of epigenetics and chromatin dynamics developed exponentially over the last decade, revealing numerous molecular mechanisms. However, some aspects of chromatin organisation remain obscure. In particular, chromatin organisation in gametes remains poorly understood, as does it role during fertilisation and early embryonic development. A better understanding of chromatin organisation would contribute to the fields of medically assisted procreation, cancer biology and regenerative medicine.
For almost 10 years, we have been involved in research projects characterising various aspects of chromatin dynamics during gametogenesis. Through these projects we investigated the final steps in reorganisation of the sperm nucleus using a unique combination of proteomics and functional assays. These projects were possible thanks to a close collaboration with Saadi Khochbin’s research group (Web site). Following these studies, the EpiGam project is an ambitious and innovative research programme ongoing at EDyP.
Taking up the challenge of characterizing ultra-modified proteins
Coordinator: Delphine Pflieger, CNRS researcher
After several years of research in Evry dedicated to the deciphering of intracellular signaling cascades relayed by dynamic phosphorylations, Delphine Pflieger joined the EDyP team at the end of 2014 to more specifically study the intricate combinations of post-translational modifications (PTMs) that can decorate proteins and impact their properties (enzymatic activity, stability, interactions with other proteins, etc). Histones constitute very complex examples of highly modified proteins, with more than 20 different types of PTMs described to date. It is also very probable that the list still contains undiscovered modifications, whose study could help better understand the complex regulation of histones and of events occurring within the chromatin environment.
Our projects that aim to identifying new PTMs on yeast histones and assess their conservation during evolution require adapting and optimizing proteomics strategies, at different levels of the analytical pipeline: protein sample preparation, mass spectrometry analysis and bioinformatic interpretation of the acquired data. The study of proteins highly modified by diverse types of PTMs and the deciphering of their possible interplay now constitute a challenge that the worldwide proteomics community has only started addressing.