Abstract
The cohesin protein complex mediates sister chromatid cohesion and participates in transcriptional control of genes that regulate growth and development. Substantial reduction of cohesin activity alters transcription of many genes without disrupting chromosome segregation. Drosophila Nipped-B protein loads cohesin onto chromosomes, and together Nipped-B and cohesin occupy essentially all active transcriptional enhancers and a large fraction of active genes. It is unknown why some active genes bind high levels of cohesin and some do not. Here we show that the TBPH and Lark RNA-binding proteins influence association of Nipped-B and cohesin with genes and gene regulatory sequences. In vitro, TBPH and Lark proteins specifically bind RNAs produced by genes occupied by Nipped-B and cohesin. By genomic chromatin immunoprecipitation these RNA-binding proteins also bind to chromosomes at cohesin-binding genes, enhancers, and Polycomb response elements (PREs). RNAi depletion reveals that TBPH facilitates association of Nipped-B and cohesin with genes and regulatory sequences. Lark reduces binding of Nipped-B and cohesin at many promoters and aids their association with several large enhancers. Conversely, Nipped-B facilitates TBPH and Lark association with genes and regulatory sequences, and interacts with TBPH and Lark in affinity chromatography and immunoprecipitation experiments. Blocking transcription does not ablate binding of Nipped-B and the RNA-binding proteins to chromosomes, indicating transcription is not required to maintain binding once established. These findings demonstrate that RNA-binding proteins help govern association of sister chromatid cohesion proteins with genes and enhancers.
Highlights
The cohesin complex plays crucial roles in sister chromatid cohesion, chromosome segregation, DNA repair, and gene transcription [1,2,3]
Nipped-B and cohesin preferentially bind a subset of genes important for growth and development, and small changes in cohesin activity cause severe birth defects
We find that the Drosophila TBPH and Lark RNA-binding proteins bind RNA produced by genes that bind Nipped-B and cohesin
Summary
The cohesin complex plays crucial roles in sister chromatid cohesion, chromosome segregation, DNA repair, and gene transcription [1,2,3]. In Drosophila, mice and humans, mutations that reduce Nipped-B dosage by less than 30%, or that slightly alter cohesin subunit structure, cause reduced growth, structural abnormalities and intellectual deficits [2, 5,6,7]. In humans, these genetic diseases are collectively called cohesinopathies, and include Cornelia de Lange Syndrome (CdLS). Heterozygous Nipped-B, NIPBL, or Nipbl mutations do not measurably alter sister chromatid cohesion or chromosome segregation, and the diverse developmental deficits likely reflect hundreds of changes in gene expression [7, 11,12,13,14]
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