An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype

Abstract

Three-dimensional genome organization, specifically organization of heterochromatin at the nuclear periphery, coordinates cell type-specific gene regulation. While defining various histone modifications and chromatin-associated proteins in multiple cell types has provided important insights into epigenetic regulation of gene expression and cellular identity, peripheral heterochromatin has not been mapped comprehensively and relatively few examples have emerged detailing the role of peripheral heterochromatin in cellular identity, cell fate choices, and/or organogenesis. In this study, we define nuclear peripheral heterochromatin organization signatures based on association with LAMIN B1 and/or dimethylation of lysine 9 on H3 (H3K9me2) across thirteen human cell types encompassing pluripotent stem cells, intermediate progenitors and differentiated cells from all three germ layers. Genomic analyses across this atlas reveal that lamin-associated chromatin is organized into at least two different compartments, defined by differences in genome coverage, chromatin accessibility, residence of transposable elements, replication timing domains, and gene complements. Our datasets reveal that only a small subset of lamin-associated chromatin domains are cell type invariant, underscoring the complexity of peripheral heterochromatin organization. Moreover, by integrating peripheral chromatin maps with transcriptional data, we find evidence of cooperative shifts between chromatin structure and gene expression associated with each cell type. This atlas of peripheral chromatin provides the largest resource to date for peripheral chromatin organization and a deeper appreciation for how this organization may impact the establishment and maintenance of cellular identity.

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.…”

To be or not be (in the LAD): emerging roles of lamin proteins in transcriptional regulation

“…In addition, KODs are depleted of active enhancers but enriched in ‘poised' and tissue-specific enhancers that can become activated upon mESC differentiation. Strikingly, it has been recently reported that certain enhancers in humans, but not their dependent promoters, gain and lose LAD occupancy in a cell type-specific manner, thus reinforcing the concept that LADs are dynamic domains implicated in cell type specification by ‘priming' and ‘poisoning' regulatory elements during cell differentiation [ 64 ]. Together, these findings support that lamins organize 3D chromatin interaction networks at several layers including: active/inactive TADs, enhancer activity and promoter interactions, which all subsequently modulate transcription inside and outside LADs during cell differentiation.…”

Restructuring of Lamina-Associated Domains in Senescence and Cancer

“…LADs are heterogeneous in their composition, dynamics, and transcriptional status ( Figure 1 A). Nevertheless, most LADs are well conserved across cell types and during differentiation [ 20 , 21 , 22 , 23 ]. Such constitutive LADs (cLADs) display the strongest LMNB1 enrichment, they are AT rich, enriched in long interspersed elements (LINEs), and strongly heterochromatic.…”

“…Variable (v)LADs arise during differentiation and therefore differ between cell types [ 19 ] ( Figure 1 A). vLADs emerge or disappear as entire domains or as edges of LADs that gain or lose contact with the NL [ 25 ], often but not always in line with the activation of cell type-specific genes within them [ 20 , 21 , 25 , 27 , 28 ]. Some vLADs are radially repositioned in the nucleus when losing NL association [ 29 ] but this is not always the case [ 27 , 30 ].…”