Local euchromatin enrichment in lamina-associated domains anticipates their repositioning in the adipogenic lineage

Abstract

Background Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confer structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains, however, elusive. Results We examined changes in the association of lamin B1 with the genome in the first 72 h of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. Lastly, we link differentially expressed genes in LADs to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation. Conclusions We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment.

Biology and Model Predictions of the Dynamics and Heterogeneity of Chromatin-Nuclear Lamina Interactions

“…Some loci in vLADs are repositioned away from the NL when they lose lamin association ( Reddy et al, 2008 ), but this is not systematic ( Robson et al, 2016 ; Forsberg et al, 2019 ; Czapiewski et al, 2022 ). LAD repositioning also occasionally concurs with activation of cell type-specific genes ( Peric-Hupkes et al, 2010 ; Robson et al, 2016 ; Keough et al, 2020 ; Czapiewski et al, 2022 ; Madsen-Østerbye et al, 2022 ) or disease-specific genes ( Kohler et al, 2020 ). vLADs may also function as regulators of transcription by releasing enhancers that in turn regulate expression of neighboring genes ( Robson et al, 2016 ; Czapiewski et al, 2022 ) ( Figure 1C ).…”

“…LADs are a general feature of genome organization, but not all LADs have similar properties ( Figure 1B ). Some are well conserved between cell types ( Keough et al, 2020 ; Meuleman et al, 2013 ), during differentiation ( Madsen-Østerbye et al, 2022 ; Peric-Hupkes et al, 2010 ; Rønningen et al, 2015 ) and across circadian time ( Brunet et al, 2019 ). These constitutive LADs (cLADs) are characterized by high lamin B1-chromatin contact frequency and are viewed as the genomic backbone of chromosome anchoring to the nuclear envelope.…”

“…Variable (v)LADs are smaller than cLADs, display lower lamin B1 enrichment, harbor a higher gene density and are less heterochromatic. vLADs are a feature of differentiation where entire LADs or LAD edges associate with or detach from the NL ( Madsen-Østerbye et al, 2022 ). Some loci in vLADs are repositioned away from the NL when they lose lamin association ( Reddy et al, 2008 ), but this is not systematic ( Robson et al, 2016 ; Forsberg et al, 2019 ; Czapiewski et al, 2022 ).…”

“…Approximately 10% of genes in cLADs have initially been found to be expressed and to escape the repressive NL environment ( Guelen et al, 2008 ), a figure which has been confirmed in many studies regardless of cell type and species. Lower local lamin B1 enrichment, promoter sequence properties and active histone modifications may account for this apparent discrepancy ( Brueckner et al, 2020 ; Leemans et al, 2019 ; Madsen-Østerbye et al, 2022 ; Wu and Yao, 2017 ) ( Figure 1D ). These regions also appear to be more prone to alterations in epigenetic states and chromatin accessibility than the more constitutive heterochromatic domains of LADs, For example, in diseases caused by lamin mutations such as Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging laminopathy caused by mutations in the LMNA gene ( Kohler et al, 2020 ; Shin and Worman, 2022 ).…”

“…We have recently assessed the extent to which basic physical properties of a polymer, such as stiffness and stretching, would influence its configurations near an impermeable (hard) surface representing a NL, fitted with an attraction potential towards the polymer ( Brunet et al, 2021 ). Chromatin is modeled as a polymer of hard beads of contour length L C 360 nm representing a ∼50 kb region to enable modeling interactions of small vLADs or euchromatic sub-LAD regions ( Madsen-Østerbye et al, 2022 ). The polymer is configured with one or two ends anchored to the surface with increasing Euclidean distance d E between them, yielding a relaxed or stretched chain ( Figure 3A ).…”