SMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells

Here, we show that SMCHD1 safeguards enhancer organization and three-dimensional (3D) genome architecture in human myoblasts. Loss of SMCHD1 leads to widespread gains in chromatin accessibility, aberrant transcriptional changes, and a global redistribution of the myogenic transcription factor MYOD1.

Integrative analyses of histone modifications, chromatin accessibility, Hi-C looping, and Activity-by-Contact enhancer–gene modeling reveal that SMCHD1 deletion rewires the landscape of clustered enhancers and promotes the emergence of a MYOD1-related network of enhancer elements, termed MYOD1 enhancer Nexuses. These structures are marked by increased enhancer–enhancer connectivity, increased local 3D chromatin interactions, and coordinated activation of myogenic and FSHD-associated genes.