Upon characterizing the nature of the chromatin that forms on telomeres, we realized that, depending on the cell type, the histone methyltransferase SETDB1 was responsible for local heterochromatinization. Counterintuitively, we found that this heterochromatin was permissive to transcription and a recombination based mode of telomere maintenance named ALT (Alternative lenghtening of telomeres), present in a subset of human cancers. We have described these results in 2019 in Science Advances (data presented at the EMBO telomere meeting in 2018, the Cold Spring Harbor Asia Temoere meeting in 2018). These unexpected results opened novel questions: the heterochromatin discovered at telomeres is better known to drive the silencing of some transposable elements in the same cells and therefore we embarked on trying to address the major differences found on SETDB1 controlled telomeres and on SETDB1 controlled transposable elements. We have developped a novel version of a locus specifc chromatin capture approach that allowed us to purify transposable elements of the Intracisternal A PArticle type (IAP). Surprisingly we found that the heterochromatin components at IAP are not much different from the heterochromatin components found at the telomeres with the exception of only a handful factors. We have focused our studies on these factors.
-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 have presented our latest data on this at the CHSL Transposon meeting in Oct 2020 and at the MBSJ in October 2021. We are finalizing some experiments to be able to publish these data
-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 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: and we therefore decided not to pursue this at the moment.
-Our serendipitous discovery of the mechanisms responsible for t-loop formation at telomeric heterochromatin is the subject of a scientific article under review at Science.
