Dataset Information

Csde1 binds transcripts involved in protein homeostasis and controls their expression in erythropoiesis

ABSTRACT: The RNA binding protein Csde1 (Cold shock domain protein e1) is strongly upregulated during erythropoiesis, but its expression is reduced in Diamond Blackfan Anemia (DBA). To understand the role of Csde1 in DBA, and the cellular pathways controlled by Csde1 in erythropoiesis, we identified the transcripts that physically associate with Csde1. These mainly encoded proteins involved in ribogenesis, mRNA translation and protein degradation, but also proteins associated with the mitochondrial respiratory chain and mitosis. Crispr/Cas9-mediated deletion of the first cold shock domain of Csde1 affected RNA expression and/or protein expression of Csde1-bound transcripts. Protein expression of ribogenesis factors Rpf2, Nop56 and Ebna1bp2 was reduced in the deletion mutant, while mRNA was unchanged. Protein expression of Pabpc1 was enhanced while Pabpc1 mRNA expression was reduced. Strikingly, the effect of reduced Csde1 function on mRNA stability and translation of Csde1-bound transcripts was modest. The correlation efficient between protein (iBAQ) and mRNA (RPKM) expression was not different between Csde1-bound and other transcripts. We suggest that Csde1 is involved in feed-back control in protein homeostasis and that it dampens oscillations in gene expression.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Blood

SUBMITTER: Kat Moore

LAB HEAD: Alexander B Meijer

PROVIDER: PXD006358 | Pride | 2018-10-24

REPOSITORIES: Pride

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Publications

Strap associates with Csde1 and affects expression of select Csde1-bound transcripts.

Moore Kat S KS Yagci Nurcan N van Alphen Floris F Meijer Alexander B AB 't Hoen Peter A C PAC von Lindern Marieke M

PloS one 20180823 8

Erythropoiesis is regulated at many levels, including control of mRNA translation. Changing environmental conditions, such as hypoxia or the availability of nutrients and growth factors, require a rapid response enacted by the enhanced or repressed translation of existing transcripts. Cold shock domain protein e1 (Csde1/Unr) is an RNA-binding protein required for erythropoiesis and strongly upregulated in erythroblasts relative to other hematopoietic progenitors. The aim of this study is to iden ...[more]

PMID: 30138317

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Project description:Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation, and affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript, soluble and insoluble protein levels were increased. In more vulnerable cerebellum the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated selective induction of Fbxw8 in old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissue-specific effects, which may be partially alleviated by the induction of FBXW8. Factorial design comparing Atxn2 knock-in mice with wild type littermates in three different tissues (brainstem, cerebellum, liver)

Dataset Information

Csde1 binds transcripts involved in protein homeostasis and controls their expression in erythropoiesis

Publications

Strap associates with Csde1 and affects expression of select Csde1-bound transcripts.

Similar Datasets

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