TY - JOUR
T1 - An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo
AU - Man, Joyce C.K.
AU - Mohan, Rajiv A.
AU - Boogaard, Malou van den
AU - Hilvering, Catharina R.E.
AU - Jenkins, Catherine
AU - Wakker, Vincent
AU - Bianchi, Valerio
AU - Laat, Wouter de
AU - Barnett, Phil
AU - Boukens, Bastiaan J.
AU - Christoffels, Vincent M.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.
AB - Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.
UR - http://www.scopus.com/inward/record.url?scp=85074283939&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12856-5
DO - 10.1038/s41467-019-12856-5
M3 - Article
C2 - 31666509
AN - SCOPUS:85074283939
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4943
ER -