Gene Regulatory Interactions at Lamina-Associated Domains

Abstract

The nuclear lamina provides a repressive chromatin environment at the nuclear periphery. However, whereas most genes in lamina-associated domains (LADs) are inactive, over ten percent reside in local euchromatic contexts and are expressed. How these genes are regulated and whether they are able to interact with regulatory elements remain unclear. Here, we integrate publicly available enhancer-capture Hi-C data with our own chromatin state and transcriptomic datasets to show that inferred enhancers of active genes in LADs are able to form connections with other enhancers within LADs and outside LADs. Fluorescence in situ hybridization analyses show proximity changes between differentially expressed genes in LADs and distant enhancers upon the induction of adipogenic differentiation. We also provide evidence of involvement of lamin A/C, but not lamin B1, in repressing genes at the border of an in-LAD active region within a topological domain. Our data favor a model where the spatial topology of chromatin at the nuclear lamina is compatible with gene expression in this dynamic nuclear compartment.

PML modulates epigenetic composition of chromatin to regulate expression of pro-metastatic genes in triple-negative breast cancer

“…A similar pattern of LMNB1 coverage was described in LADs, where local euchromatic and lamin-depleted sub-domains were found to contain differentially expressed genes ( 53 , 57 ). Similarly, local euchromatic and PML-depleted sub-domains (named PADs sub-domains) were depleted of H3K9me3 and LMNB1 compared to the rest of PADs (Figure 5A , C ), suggesting evasion from the overall heterochromatic state.…”

“…Specifically, mosaic distribution of H3K9me3 within heterochromatic domains allows isolation of euchromatic regions where productive interactions between regulatory elements and gene promoters drive transcription ( 78 ). Similarly, LADs contain enhancer-rich domains of low LMNB1 association and active transcription where gene expression is regulated by constraining short or long-range promoter-enhancer interactions ( 52 , 57 , 79 , 80 ). In sum, our results are in line with mounting evidence showing that some genes residing into constitutive heterochromatin require the surrounding repressive environment for proper expression ( 78 ).…”

Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts

“…This suggests that these properties are not defined by cell type or lamin interactions but rather by gene expression, underlying epigenetic states, or DNA sequence [81][82][83]. Regardless, these findings support increasing evidence of chromatin regulation and gene expression control in LADs [25,84,85] that are uncoupled from association with the nuclear lamina [86,87].…”

The molecular basis of lamin-specific chromatin interactions

“…Here, we revealed the alteration in spatial nucleosome concentration at the NE and as a consequence of the knockout of specific types of lamins in MEFs. Chromatin at the NL, primarily consisting of LADs, is enriched with heterochromatin histone methylation marks and only hosts a small fraction of expressed genes 52 . However, our data revealed a variation in the concentration of nucleosomes at the NE, which may correlate with more open chromatin, typically associated with expressed genes.…”