Maintenance of Silent Chromatin through Replication Requires SWI/SNF-like Chromatin Remodeler SMARCAD1

Abstract

Epigenetic marks such as posttranslational histone modifications specify the functional states of underlying DNA sequences, though how they are maintained after their disruption during DNA replication remains a critical question. We identify the mammalian SWI/SNF-like protein SMARCAD1 as a key factor required for the re-establishment of repressive chromatin. The ATPase activity of SMARCAD1 is necessary for global deacetylation of histones H3/H4. In this way, SMARCAD1 promotes methylation of H3K9, the establishment of heterochromatin, and faithful chromosome segregation. SMARCAD1 associates with transcriptional repressors including KAP1, histone deacetylases HDAC1/2 and the histone methyltransferase G9a/GLP and modulates the interaction of HDAC1 and KAP1 with heterochromatin. SMARCAD1 directly interacts with PCNA, a central component of the replication machinery, and is recruited to sites of DNA replication. Our findings suggest that chromatin remodeling by SMARCAD1 ensures that silenced loci, such as pericentric heterochromatin, are correctly perpetuated.

Keeping chromatin quiet

“…9,[16][17][18][19] Depletion of the WICH complex, comprising SNF2h and the Williams Syndrome Transcription Factor WSTF, is accompanied by an increase in heterochromatin marks following S phase. 17 WICH seems to be responsible for keeping chromatin accessible after its assembly.…”

“…9,10 Heterochromatin promotes genome stability by repressing transcription and illegitimate recombination between repetitive DNA elements. 20,21 In particular, heterochromatic repeats flanking centromeres are important for centromere function, mediating proper chromosome segregation.…”

“…4,15,16 Mi-2/NuRD emphasis of this review is on new work that places nucleosome remodeling as one of the earliest steps in the reassembly of functional chromatin domains after replication and provides mechanistic insights into how this is achieved. 9,10 ATP-Dependent Remodelers Play Integral Roles during Replication ATP-dependent chromatin remodeling is typically performed by multi-protein complexes with a conserved catalytic core related to the yeast SWI/SNF ATPase. 3 This constitutes a large group of enzymes which exert their distinct functions upon hydrolysis of ATP to drive transitions in chromatin structure.…”

Genome-wide linkage analysis and whole-genome sequencing identify a recurrent SMARCAD1 variant in a unique Chinese family with Basan syndrome

“…2 Nine pedigrees with Basan syndrome have been reported worldwide. [3][4][5][6][7][8][9][10] Recently, Marks et al 10 identified SMARCAD1 (OMIM 612761) as a promising candidate gene for Basan syndrome in an American family. This gene encodes a member of the SNF subfamily of helicase proteins.…”

“…This gene encodes a member of the SNF subfamily of helicase proteins. 9 Variants in the SMARCAD1 gene were previously reported in patients with adermatoglyphia (ADG, OMIM 136000), which is characterized by the congenital absence of epidermal ridges. 11,12 To date, five variants (c.378+1G4T, c.378+1G4A, c.378+2T4C, c.378+3A4T and c.378 +5G4C) have been reported in patients with ADG and Basan syndrome.…”