Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs

Abstract

Summary It is largely unclear whether genes that are naturally embedded in lamina-associated domains (LADs) are inactive due to their chromatin environment or whether LADs are merely secondary to the lack of transcription. We show that hundreds of human promoters become active when moved from their native LAD position to a neutral context in the same cells, indicating that LADs form a repressive environment. Another set of promoters inside LADs is able to “escape” repression, although their transcription elongation is attenuated. By inserting reporters into thousands of genomic locations, we demonstrate that escaper promoters are intrinsically less sensitive to LAD repression. This is not simply explained by promoter strength but by the interplay between promoter sequence and local chromatin features that vary strongly across LADs. Enhancers also differ in their sensitivity to LAD chromatin. This work provides a general framework for the systematic understanding of gene regulation by repressive chromatin.

Local rewiring of genome–nuclear lamina interactions by transcription

“…These and previously reported data (Gonzalez-Sandoval & Gasser, 2016;van Steensel & Belmont, 2017;de Leeuw et al, 2018;Kim et al, 2019;Lochs et al, 2019) together suggest a balancing act between transcription and LADs: For many genes, LADs pose a repressive environment (Leemans et al, 2019). This, however, may be overcome by strong transcription activators.…”

“…In support of such an additional mechanism, some of the genes that we studied (e.g., Figs A and A, and A) showed the strongest loss of NL interactions near their 5′ end. Similarly, a class of naturally active genes inside LADs exhibits more prominent detachment of their TSS compared to the downstream transcription units (preprint: Luperchio et al , ; Wu & Yao, ; Leemans et al , ). Furthermore, global tethering of VP64 across all LADs caused virtually no changes in transcription yet triggered loosening of LAD‐NL interactions (Kind et al , ), underscoring that VP16 can counteract NL interactions without activating transcription.…”

“…These observations raise the interesting possibility that the NL helps to establish a repressive environment. In support of this notion, depletion of lamins can lead to derepression of specific genes (primarily in Drosophila ) (Shevelyov et al , ; Kohwi et al , ; Chen et al , ); transfer of human inactive promoters from LADs to a neutral chromatin environment can lead to activation of these promoters (Leemans et al , ); and artificial tethering of some genes to the NL can reduce their activity (Finlan et al , ; Kumaran & Spector, ; Reddy et al , ; Dialynas et al , ).…”

“…Most genes inside LADs have very low transcriptional activity (Guelen et al, 2008;Peric-Hupkes et al, 2010;Leemans et al, 2019). When cells differentiate, detachment of genes from the NL often coincides with transcriptional activation, while increased NL interactions correlate with reduced transcription (Peric-Hupkes et al, 2010;Lund et al, 2013;Robson et al, 2016Robson et al, , 2017.…”

SPIN reveals genome-wide landscape of nuclear compartmentalization

“…In this implementation of SPIN to infer genome-wide nuclear compartmentalization patterns, we used TSA-seq and DamID mapping data in K562 for nuclear speckles (TSA-Seq), lamina (DamID and TSA-Seq), and nucleoli (DamID). Nucleoli DamID data, generated using a Dam methylase fusion with a nucleolar targeting peptide repeat (4xAP3 (Scott et al, 2010)) is new; all remaining data are as published previously (Chen et al, 2018;Leemans et al, 2019). Details of the new nucleolar DamID mapping are described elsewhere (van Schaik et al manuscript in prep.).…”