Paper in Genome Research (2015)

Rønningen T., Shah A, Oldenburg AR, Vekterud K, Delbarre E, Moskaug JØ, Collas P. 2015. Prepatterning of differentiation-driven nuclear lamin A/C-associated chromatin domains by GlcNAcylated histone H2B. Genome Res 25(12):1825-35. PMID: 26359231

Dynamic interactions of nuclear lamins with chromatin through lamin-associated domains (LADs) contribute to spatial arrangement of the genome. Here, we provide evidence for pre-patterning of differentiation-driven formation of lamin A/C LADs by domains of histone H2B modified on serine 112 by the nutrient sensor O-linked N-acetylglucosamine (H2BS112GlcNAc), which we term GADs. We demonstrate a two-step process of lamin A/C LAD formation during in vitro adipogenesis, involving spreading of lamin A/C-chromatin interactions in the transition from progenitor cell proliferation to cell cycle arrest, and genome-scale redistribution these interactions through a process of LAD exchange within hours of adipogenic induction. Lamin A/C LADs are found both in active and repressive chromatin contexts which can be influenced by cell differentiation status. De novo formation of adipogenic lamin A/C LADs occurs non-randomly on GADs, which consist of megabase-size intergenic and repressive chromatin domains. Accordingly, whereas pre-differentiation lamin A/C LADs are gene-rich, post-differentiation LADs harbor repressive features reminiscent of lamin B1 LADs. Release of lamin A/C from genes directly involved in glycolysis concurs with their transcriptional upregulation after adipogenic induction, and with downstream elevations in H2BS112GlcNAc levels and O-GlcNAc cycling. Our results unveil an epigenetic pre-patterning of adipogenic LADs by GADs, suggesting a coupling of developmentally regulated lamin A/C-genome interactions to a metabolically sensitive chromatin modification.

Modeling of chromatin states reveals the dynamics of LADs and GADs during adipogenic differentiation. (A) ChromHMM emission parameters: heat map of the relative abundance of chromatin states (numbered 1–15) in each indicated chromatin mark. The four lamin A/C-containing states are labeled green (states 2, 3, 4, 15). (B) Heat map of the relative abundance of the 15 states on predefined genomic regions on D0 and D3 of differentiation. Distribution of the four lamin A/C-containing states is shown in green areas in D0. On D3, red and yellow areas depict significant reductions (red) or increases (yellow) in enrichment levels of the lamin A/C-containing states. (C) A two-step model of formation of lamin A/C LADs during adipogenic differentiation. In proliferating adipocyte progenitors, LAD coverage is limited and does not necessarily involve GADs. After cell-cycle arrest, a necessary step for adipogenic differentiation, LAD coverage is extended independently of GADs. In undifferentiated cells, lamin A/C LADs contain both repressed and active chromatin domains. Adipogenic differentiation elicits an exchange of lamin A/C LADs; this involves the formation of LADs predominantly on H2BGlcNAc domains, consistent with an epigenetic prepatterning of de novo adipogenic lamin A/C LADs by GADs. The involvement of H3K27me3-enriched regions in LAD borders on the maintenance of LADs in mouse cells raises the possibility that de novo lamin A/C LADs formed during adipogenesis also entail a contribution from trimethylated H3K27 in LAD borders. The overall repressed state of these de novo LADs, together with their strong overlap with lamin B1 LADs, suggests that they become enriched in heterochromatin marked by di- or trimethylated H3K9.



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