Chromatin changes in SMARCAL1 deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia.
Mutations in SMARCAL1, 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 between Marcal1, the Drosophila melanogaster ortholog of SMARCAL1, and the genes of the trithorax group (trxG) and Polycomb group (PcG), which encode epigenetic regulators. SMARCAL1 and Marcal1 genetically interacted with trxG and PcG members. A homozygous null mutation of Marcal1 suppressed the wing-to-haltere transformation, ectopic Ultrabithorax (Ubx) expression, and ectopic Ubx minigene expression caused by PcG deficiency. The suppression of ectopic Ubx expression correlated with reduced chromatin accessibility of the Ubx promoter. To our knowledge, this is the first in vivo evidence for deficiency of a SMARCAL1 ortholog altering the chromatin structure of a gene.
a Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
Marie
M
Morimoto
a Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
Kunho
K
Choi
a Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
Cornelius F
CF
Boerkoel
b Department of Biological Sciences , Konkuk University , Seoul , Republic of Korea.
Kyoung Sang
KS
Cho
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004265:DNA Helicases / Q000172:deficiency* / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism / Q000235:genetics* / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; C066177:Ubx protein, Drosophila; C412482:SMARCAL1 protein, human; D004265:DNA Helicases
Drosophila melanogaster; Polycomb group; SMARCAL1; Schimke immuno-osseous dysplasia; Ultrabithorax; chromatin structure; epigenetics; trithorax group