GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE319nnn/GSE319422/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE319422GEOGSEfalseSMCHD1 loss re-wires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells [ChIP-seq]Human SMCHD1 is a chromatin architectural regulator linked to facioscapulohumeral muscular dystrophy (FSHD), but how SMCHD1 regulates myogenic transcription independently of DUX4 remains unclear. 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. Together, our findings identify SMCHD1 as a key architectural constraint that suppresses hyperactive enhancer networks, thereby preserving transcriptional homeostasis in myoblasts.2026/09/11GSE319422GSM9517644GSM9517643GSM9517646GSM9517645GSM951764716791319422Homo sapiens