Depletion of lamin-associated polypeptide 2 alpha leads to chromatin reorganization and redistribution of A-type lamins to open genomic regions [ATAC-seq]

Background: Lamins are major regulators of the spatial and functional organization of chromatin. Lamins at the nuclear periphery form the lamina that anchors heterochromatin to the nuclear envelope. A subpool of A-type lamins localizes in the nuclear interior, where they also bind to euchromatic genomic regions. A-type lamin properties and chromatin association are regulated by lamin-associated polypeptide 2alpha (LAP2α). Here we systematically analyze, how LAP2α depletion affects chromatin organization, accessibility and gene expression on a genome-wide level. Results: LAP2α depletion in mouse dermal fibroblasts positively and negatively affects chromatin accessibility and gene expression throughout the genome, which correlates with changes in chromatin association of A-type lamins and the nucleosomal remodeler proteins BRG1 and CHD4. In particular, A-type lamins translocate to open chromatin regions closer to BRG1 and CHD4 binding sites and deregulated genes, but do not directly accumulate on genes and BRG1 and CHD4-enriched sites. Unsupervised clustering of the datasets on LAP2α-bound genomic regions confirms spreading of A-type lamins to active chromatin regions containing deregulated genes, and an enrichment of chromatin remodelers on a subset of these genomic regions. Conclusions: LAP2α depletion in fibroblasts leads to a gross rearrangement of chromatin. Genome-wide chromatin reorganization is linked to spreading of A-type lamins to active chromatin regions and accompanied by a restriction of chromatin remodelers to a subset of active genomic regions. These changes correlate with changes in chromatin accessibility and gene expression throughout the genome and particularly in regions, where lamin binding is gained in LAP2α knockout versus wildtype cells. This research was funded in whole or in part by the Austrian Science Fund (FWF) [P32512-B and P36503-B] to Roland Foisner, and a doctorate program funded by the Austrian Science Fund (FWF) [W1261-B28]. Daria Filipczak is recipient of a DOC Fellowship of the Austrian Academy of Sciences (ÖAW DOC 25912); This work is also supported by a Marie Jahoda fellowship of the University of Vienna to Nana Naetar.