Chromatin protein complexes involved in gene repression in lamina-associated domains

Lamina-associated domains (LADs) are large chromatin regions that are associated with the nuclear lamina (NL) and form a repressive environment for transcription. The molecular play-ers that mediate gene repression in LADs are currently unknown. Here we performed FACS-based whole-genome genetic screens in human cells using LAD-integrated fluorescent re-porters to identify such regulators. Surprisingly, the screen identified very few NL proteins, but revealed roles for dozens of known chromatin regulators. Among these are the negative elongation factor (NELF) complex and interacting factors involved in RNA polymerase paus-ing, suggesting that regulation of transcription elongation is a mechanism to repress tran-scription in LADs. Furthermore, the chromatin remodeler complex BAF and the activation complex Mediator can work both as activators and repressors in LADs, depending on the local context and possibly rewiring of heterochromatin. Our data clearly emphasize that the fundamental regulatory steps of the transcription process and chromatin remodeling factors, rather than interaction with NL proteins, play a major role in the regulation of transcription within LADs.