Abstract
SUMMARYNIPBL, a cohesin loader, has been implicated in transcriptional control and genome organization. Mutations in NIPBL, cohesin, and its deacetylase HDAC8 result in Cornelia de Lange syndrome. We report activation of the RNA-sensing kinase PKR in human lymphoblastoid cell lines carrying NIPBL or HDAC8 mutations, but not SMC1A or SMC3 mutations. PKR activation can be triggered by unmodified RNAs. Gene expression profiles in NIPBL-deficient lymphoblastoid cells and mouse embryonic stem cells reveal lower expression of genes involved in RNA processing and modification. NIPBL mutant lymphoblastoid cells show reduced proliferation and protein synthesis with increased apoptosis, all of which are partially reversed by a PKR inhibitor. Non-coding RNAs from an NIPBL mutant line had less m6A modification and activated PKR activity in vitro. This study provides insight into the molecular pathology of Cornelia de Lange syndrome by establishing a relationship between NIPBL and HDAC8 mutations and PKR activation.
Highlights
Chromosomes undergo structural changes to facilitate gene expression and genome organization
With over 60% of Cornelia de Lange syndrome (CdLS) cases associated with Nipped B-like protein (NIPBL) mutations, the etiology of CdLS can likely be at least partially elucidated by studying the loss of function of NIPBL
To investigate the potential functions of NIPBL, we first analyzed the publicly available data of chromatin immunoprecipitation (ChIP) followed by massive parallel deep sequencing (ChIP-seq) of NIPBL in human lymphoblastoid cell lines (LCLs) (Sequence Read Archive [SRA]: ERR139553)
Summary
Chromosomes undergo structural changes to facilitate gene expression and genome organization. These changes are regulated, in part, by structural maintenance of chromosome (SMC) proteins. SMC proteins are evolutionarily conserved complexes that regulate the structural and functional organization of chromosomes from bacteria to humans (Nasmyth and Haering, 2005). SMC proteins are an essential component of complexes that organize chromosomes in the nucleus through the utilization of energy from ATP hydrolysis (Hirano, 2006). One of the SMC complexes, cohesin, is composed of four subunits including a heterodimer of SMC1A and SMC3 along with the kleisin RAD21. The cohesin complex is crucial for various biological processes, such as chromosome segregation, condensation, gene expression, and double-strand break repair (Jeppsson et al, 2014)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have