Transcriptional dysregulation associated with chromatin accessibility of iPSC and hepatocytes derived from a Cornelia de Lange syndrome patient (scRNA-Seq) [N]
Cornelia de Lange syndrome (CdLS) is a rare genetic disease associated with cohesinopathy.  A  novel iPSC line was generated from the CdLS patient carrying a heterozygous missense point-mutation of the  NIPBL gene.  iPSC lines prepared from the healthy parents and the mutation-corrected isogenic cell lines are used as the respective controls.  Upon differentiation into hepatocytes, the patient-derived iPSC demonstrate the capacity to express hepatocyte-specific marker transcripts and the respective proteins, however, the efficiency of differentiation is significantly inferior to those of the respective controls, demonstrated by single-cell RNA sequencing and immune-fluorescent analyses.  Global change of transcriptome in the patient-derived iPSC relative to the control cells is associated with altered chromatin accessibility, assessed by RNAseq combined with ATACseq analysis.   Differentially down-regulated genes in the patient-derived iPSC, in particular, are those coding for proteins related to neural differentiation and transcription factors, while up-regulated genes contain some of antisense RNA coding genes, pseudo genes and long non-coding RNAs.  Some of the differentially regulated genes are consistent with the altered chromatin accessibility and this observation is consistent during hepatocyte differentiation.  Thus, the mutation in the NIPBL gene of the CdLS patient could be responsible for defects of differentiation primarily due to alteration of chromatin accessibility.