6ème Rencontre scientifique des Grands Causses

H. Flow, a 3D animation explaining how repeat sequences drive genome organization and condition gene expression

Non programmé

20m

Oral

Orateur

genevieve fourel (INSERM)

Description

Over 20 years ago, the scientific community identified the general mechanistic principles governing the establishment of open or closed chromatin domains in a given region of the eukaryotic genome, which either permit or prevent the expression of the underlying genes, respectively (1-5). The clustering of domains predominantly harboring closed chromatin forms the heterochromatin compartment, also known as the B compartment, while open chromatin forms the euchromatin or A compartment. This partitioning of chromatin within the nucleus was first observed by E. Heitz in the early 20th century using microscopy (6).
It was discovered that key to this partitioning are short DNA elements capable of nucleating and anchoring heterochromatin material (ProB elements) or, conversely, counteracting its assembly at the nucleosomal fiber, thereby seemingly repelling B-type chromatin (ProA elements) (1-5).
We showed that ProA and ProB elements are derived from repeat sequences (RepSeqs), in human and likely in all higher eukaryotes (7). In human, constitutive ProA RepSeqs are predominantly composed of Alu elements, whereas constitutive ProB RepSeqs consist of young L1s, some Endogenous Retroviruses (ERVs) and a panel of satellite DNA sequences, including AT-rich microsatellites, pericentromeric and subtelomeric satellites. Additionally, RepSeqs of all types with more indefinite character and, importantly, their derivatives known as "transcriptional enhancers", can switch between ProA and ProB functions and thereby act to open or close specific chromatin domains depending on the cellular context.
It thus appears that a major and previously unrecognized function of repeat sequences, which constitute the majority of the genome in higher eukaryotes, is to organize the genome into two distinct compartments, euchromatin and heterochromatin. This process is essential for the regulation of gene expression during cell differentiation and development, and for the prevention of diseases, most notably cancer.

While the key players have thus been identified, the mechanisms by which repeat sequences organize the genome and the molecular dynamics involved remain unclear. We will address this question through a 15-minute 3D animated video.

1. Fourel G, Lebrun E, Gilson E. 2002. Protosilencers as building blocks for heterochromatin. Bioessays 24:828-35.
2. Fourel G, Magdinier F, Gilson E. 2004. Insulator dynamics and the setting of chromatin domains. Bioessays 26:523-32.
3. Oki M, Valenzuela L, Chiba T, Ito T, Kamakaka RT. 2004. Barrier proteins remodel and modify chromatin to restrict silenced domains. Mol Cell Biol 24:1956-67.
4. Dhillon N, Kamakaka RT. 2024. Transcriptional silencing in Saccharomyces cerevisiae: known unknowns. Epigenetics Chromatin 17:28.
5. Dodd IB, Sneppen K. 2011. Barriers and silencers: a theoretical toolkit for control and containment of nucleosome-based epigenetic states. J Mol Biol 414:624-37.
6. Heitz E. 1935. Chromosomenstruktur und Gene. Z Indukt Vererb 70:402-447.
7. Bonnet KA, Hulo N, Mourad R, Ewing A, Croce O, Naville M, Vassetzky N, Gilson E, Picard D, Fourel G. 2023. ProA and ProB repeat sequences shape genome organization, and enhancers open domains. bioRxiv doi:10.1101/2023.10.27.564043:2023.10.27.564043.