Unknown,Transcriptomics,Genomics,Proteomics

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Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3)

ABSTRACT: Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila, and mouse models, we show that the proteins encoded by SMARCAL1 orthologues localize to transcriptionally active chromatin and modulate gene expression. We also show that similar to SIOD patients, deficiency of the SMARCAL1 orthologues alone is insufficient to cause disease in fruit flies and mice although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD. The RNA sequencing libraries were constructed from the liver RNA of 3-4-month Smarcal1del/del and wt female mice (n=3/group) at 20M-BM-0C and after 1 hour at 39.5M-BM-0C. These libraries were sequenced using the whole transcriptome shotgun sequencing procedure.

ORGANISM(S): Mus musculus

SUBMITTER: Alireza Baradaran-Heravi

PROVIDER: E-GEOD-35553 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression.

Baradaran-Heravi Alireza A Cho Kyoung Sang KS Tolhuis Bas B Sanyal Mrinmoy M Morozova Olena O Morimoto Marie M Elizondo Leah I LI Bridgewater Darren D Lubieniecka Joanna J Beirnes Kimberly K Myung Clara C Leung Danny D Fam Hok Khim HK Choi Kunho K Huang Yan Y Dionis Kira Y KY Zonana Jonathan J Keller Kory K Stenzel Peter P Mayfield Christy C Lücke Thomas T Bokenkamp Arend A Marra Marco A MA van Lohuizen Maarten M Lewis David B DB Shaw Chad C Boerkoel Cornelius F CF

Human molecular genetics 20120228 11

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficien ...[more]

PMID: 22378147

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Project description:It is unclear how epigenetic changes regulate the induction of erythroid-specific genes during terminal erythropoiesis. Here we use global mRNA sequencing (mRNA-seq) and chromatin immunoprecipitation coupled to high-throughput sequencing (CHIP-seq) to investigate the changes that occur in mRNA levels, RNA Polymerase II (Pol II) occupancy and multiple post-translational histone modifications when erythroid progenitors differentiate into late erythroblasts. Among genes induced during this developmental transition, there was an increase in the occupancy of Pol II, the activation marks H3K4me2, H3K4me3, H3K9Ac and H4K16Ac, and the elongation methylation mark H3K79me2. In contrast, genes that were repressed during differentiation showed relative decreases in H3K79me2 levels yet had levels of Pol II binding and active histone marks similar to those in erythroid progenitors. We also found that relative changes in histone modification levels-in particular, H3K79me2 and H4K16ac-were most predictive of gene expression patterns. Our results suggest that in terminal erythropoiesis both promoter and elongation-associated marks contribute to the induction of erythroid genes, while gene repression is marked by changes in histone modifications mediating Pol II elongation. Our data maps the epigenetic landscape of terminal erythropoiesis and suggests that control of transcription elongation regulates gene expression during terminal erythroid differentiation. Mouse fetal liver cells are double-labeled for erythroid-specific TER119 and non erythroid-specific transferrin receptor (CD71) and then sorted by flow-cytometry. E14.5 fetal livers contain at least five distinct populations of cells (R1 through R5); as they progressively differentiate they gain TER119 and then gain and subsequently lose CD71. CFU-E cells and proerythroblasts make up the R1 population; R2 consists of proerythroblasts and early basophilic erythroblasts; R3 includes early and late basophilic erythroblasts; R4 is mostly polychromatophilic and orthochromatophilic erythroblasts; and R5 is comprised of late orthochromatophilic erythroblasts and reticulocytes. We have sorted for R2-R5 cells for RNA-seq experiment.

Dataset Information

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3)

Publications

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression.

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