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Final Report Summary - CHROMO-ANCHORING (Functional organization of heterochromatin at the nuclear periphery in cell differentiation)

The human body is composed of several billions of cells most of which exert different functions. All these cells derive from a common progenitor that originates as the male gamete fertilizes the egg and share an identical genomic sequence. As development progresses, cells divide and specialize to generate tissues such as muscle, intestine and brain, all of which further contain subsets of even more specialized cells. It is therefore clear that to better understand the complexity of the human body, both in health and disease, we must first understand the mechanisms that regulate cell differentiation. As stated above, all the different cells in our body share a common DNA sequence, what differentiates them is how genes within the DNA are regulated, as specific tissue differentiation programs require specific gene expression patterns. How this is achieved is a complex, fascinating and still open question.
DNA is not a naked molecule within our cells but is bound to proteins, altogether constituting chromatin. Among the core proteins within chromatin are histones that can be variously modified contributing to gene regulation. There are two main classes of chromatin, euchromatin which typically marks active genes and heterochromatin which corresponds to silenced regions. Across species, eu- and hetero- chromatin are not only distinct in their function but also occupy different locations within the nucleus. Emerging evidence suggest that the accumulation and sequestration of heterochromatin at the nuclear periphery during differentiation is involved in cell fate stabilization. H3K9 (Lysine 9 on histone H3) methylation is an essential signal for heterochromatin peripheral sequestration in C. elegans early embryos. However, with differentiation additional H3K9me-independent segregation pathways are induced.
This project aimed at identifying and characterizing these mechanisms in the context of a developing organism. We used C. elegans as model organism because the general chromatin principles governing tissue differentiation are in common with higher organisms like mammals. Nonetheless, its reduced genetic and physiological complexity is ideal to begin unveiling novel pathways.
In this study, we discovered the nuclear protein MRG-1 and H3K36 (Lysine 36 on histone H3) methylation as part of a novel, chromatin-based pathway promoting the accurate spatial segregation of eu- and hetero-chromatin in a differentiated tissue of a developing organism, namely intestine. By first taking advantage of reporters, monitored via microscopy, and then by performing genome-wide analysis of how the intestinal DNA contacts the nuclear periphery, we found that H3K9me and MRG-1/H3K36me function redundantly at some genomic sites. However, other regions are exquisitely sensitive to either one of the two pathways.
While H3K9me is a chromatin modification typically marking heterochromatin and therefore it is directly signaling for its perinuclear sequestration, MRG-1 and H3K36me are instead hallmark of euchromatic, active regions and act indirectly on heterochromatin.
Our study suggests that this mechanism involves the deregulation of other euchromatic factors, namely histone acetyl transferases (HATs), that are involved in acetylation of histones and can impact on chromatin structure. The model we propose is that MRG-1/H3K36me are key guardians of euchromatin structure and upon their perturbation HATs are mis-regulated and instead of being retained into euchromatin can inappropriately interact with heterochromatin, leading to its structural change. Remarkably, our data indicate that heterochromatin is also functionally destabilized as heterochromatic genes are de-silenced in mrg-1 and H3K36me mutants.
Our work reveals an unprecedented finding: the accurate spatial and functional segregation of heterochromatin requires equally on direct players, like H3K9me, but also on indirect euchromatin factors, that must be retained into active regions.
Our findings were unexpected and are of great originality. Moreover, since all the factors identified in this study are conserved from yeast to man, it is likely that a similar pathway exists in mammals as well, making this work of broad interest and high impact.
Understanding how euchromatin and heterochromatin identities are maintained within differentiated cells not only contributes to our basic understanding of differentiation and development but is also relevant to the field of cell reprogramming. Therefore, in this perspective, this work could have an impact on the expanding field of regenerative medicine and disease modelling approaches.

Reported by

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH
Switzerland
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