Periodic Reporting for period 3 - METACHROM (Establishment and maintenance of gene expression by heterochromatin factors)
Okres sprawozdawczy: 2020-06-01 do 2021-11-30
Our overall objectives are:
-to understand the nature and the function of the special heterochromatin that forms on telomeres and on transposable elements. We addressed the former in Gauchier et al, Science Adv. 2019. The latter is currently being addressed by two members of the team (Amandine Barral, PhD student and Mathilde Gauchier, post-doc).
-to understand the mechanistics of this heterochromatin. We have addressed this (Gohei Nishibushi) by performing the heterochromatin reconstitution experiments explained in aim2 of the proposal and are currently finalizing this part of the proposal.
-to uncover all the players involved in the metastable silencing of transposble elements in the mouse genome. We have identified a potentially crucial transposon defense mechanism
The long reaching implications of our work are in several area of fundamental research and on diseases: it is known that defective heterochromatin can lead to loss of cellular identity and cancer. Our work will aim at explaining some of the important mechanisms behind such deleterious phenomena.
-some are known to be involved in the sensing of abnormal nucleic acid molecules and to trigger an innate immune response. We are currently working on the role of these factors in the control of transposable element chromatin: Mathilde Gauchier presented the first data on this at the Cold Spring Harbor Transposon Meeting in 2018, and I and her will present our latest data on this at the upcoming CHSL Transposon meeting in Oct 2020.
-We also developped genome-wide approaches to identify all the chromosomal regions which harbor a heterochromatin which is similar to the one identified at telomeres. We have identified set of ~5,000 domains, which share the same chromatin features as the telomeres and are testing the function of this heterochromatin in the control of gene expression profiles and genome stability. We uncovered that these regions are actually critical locus control regions that are important for cellular identity. This work has just been publihsed in Molecular Cell (17 Feb 2022 issue)
-We have also reconstituted a metastable transgene to which heterochromatin can be induced and destroyed very rapidly. While the system works and highlights some differences in the type of heterochromatin that can form on a gene, we have so far, failed to create a transgenic chromatin able of memory (hence original Aim3 has been cancelled)
-Our efforts to induce durable epigenetic changes in the genome by inducing diverse types of stress on stem cells have, for the moment, yielded no clear data: at the moment we don't find any stress induced change that can be maintained after stress recovery.