Chromatin changes in SMARCAL1 deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia.

Morimoto, Marie; Choi, Kunho; Boerkoel, Cornelius F.; Cho, Kyoung Sang

Mutations inSMARCAL1, which encodes a DNA annealing helicase with roles in DNA replication fork restart, DNA repair, and gene expression modulation, cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive disease characterized by skeletal dysplasia, renal disease, T-cell immunodeficiency, and arteriosclerosis. The clinical features of SIOD arise from pathological changes in gene expression; however, the underlying mechanism for these gene expression alterations remains unclear. We hypothesized that changes of the epigenome alter gene expression in SIOD. To test this, we performed a genetic screen for interaction betweenMarcal1, theDrosophila melanogasterortholog ofSMARCAL1, and the genes of the trithorax group (trxG) and Polycomb group (PcG), which encode epigenetic regulators.SMARCAL1andMarcal1genetically interacted with trxG and PcG members. A homozygous null mutation ofMarcal1suppressed the wing-to-haltere transformation, ectopicUltrabithorax(Ubx) expression, and ectopicUbxminigene expression caused by PcG deficiency. The suppression of ectopicUbxexpression correlated with reduced chromatin accessibility of theUbxpromoter. To our knowledge, this is the firstin vivoevidence for deficiency of aSMARCAL1ortholog altering the chromatin structure of a gene.

CHROMATIN; PROTEIN deficiency; GENE expression; DYSPLASIA; GENETIC mutation; DNA replication; DNA repair

Nucleus (1949-1034), 2016, Vol 7, Issue 6, p560

1949-1034

Academic Journal

10.1080/19491034.2016.1255835