Transcriptome of the inner circular smooth muscle of the developing mouse intestine: Evidence for regulation of visceral smooth muscle genes by the hedgehog target gene, cJun

Abstract

Background Digestion is facilitated by coordinated contractions of the intestinal muscularis externa, a bilayered smooth muscle structure that is composed of inner circular (ICM) and outer longitudinal (OLM) muscles. We performed transcriptome analysis of intestinal mesenchyme tissue at E14.5, when the ICM, but not the OLM is present, to investigate the transcriptional program of the ICM. Results We identified 3967 genes enriched in E14.5 intestinal mesenchyme. The gene expression profiles were clustered and annotated to known muscle genes, identifying a muscle- enriched subcluster. Using publically available in situ data, 127 genes were verified as expressed in ICM. Examination of the promoter and regulatory regions for these co-expressed genes revealed enrichment for cJUN transcription factor binding sites and cJUN protein was enriched in ICM. cJUN ChIP-seq, performed at E14.5, revealed that cJUN regulatory regions contain characteristics of muscle enhancers. Finally, we show that cJUN is a target of Hedgehog (Hh), a signaling pathway known to be important in smooth muscle development, and identify a cJUN genomic enhancer that is responsive to Hh. Conclusions This work provides the first transcriptional catalog for the developing ICM and suggests that cJUN regulates gene expression in the ICM downstream of Hh signaling.

Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing

“…In order to identify novel causal genes, a one‐tailed binomial test was used to prioritize potential causal genes enriched for rare (MAF ≤1×10 −3 in gnomAD) and damaging dominant variants (LoF and missense variants with MetaSVM “D”) in 23 unrelated CIPO subjects as described before . Given that CIPO has an association with intestinal smooth muscle contraction and most of the identified causal genes are related with contractile apparatus, we prioritized our analysis to highly expressed genes in intestinal smooth muscle using a published RNA‐Seq dataset from mouse intestinal mesenchyme at E14.5 and defined the highly expressed intestinal smooth muscle cell genes as the top quartile human orthologs (See Supporting Methods). Through the binomial test (Table ), COL4A1, FBLN1 and HK2 show significant enrichment (FDR [False discovery rate] < 0.05 using Benjamini‐Hochberg method).…”

“…Although the cohort has been prescreened for pathogenic ACTG2 mutations, we included two subjects carrying rare missense In order to identify novel causal genes, a one-tailed binomial test was used to prioritize potential causal genes enriched for rare (MAF ≤1×10 −3 in gnomAD) and damaging dominant variants (LoF and missense variants with MetaSVM "D") in 23 unrelated CIPO subjects as described before. 15 Given that CIPO has an association with intestinal smooth muscle contraction and most of the identified causal genes are related with contractile apparatus, we prioritized our analysis to highly expressed genes in intestinal smooth muscle using a published RNA-Seq dataset from mouse intestinal mesenchyme at E14.5 16 were reported for Thoracic Aortic Aneurysm and/or aortic Dissection (TAAD) and Patent Ductus Arteriosus. 18,19 However, the proband 122 057 and his son have normal aorta through CT scan and MRA, and no family member has had an aneurysm.…”

Control of growth and gut maturation by HoxD genes and the associated lncRNA Haglr

“…In the absence of Blimp1 , for example, early enterocytes are lost prematurely, precluding growth of the organism due to the incompetence of the adult-type enterocytes to digest milk ( 21 , 22 ). Our observations suggest that, similar to Blimp1 , Hoxd3 may promote the maintenance of milk-digesting enterocytes, raising the possibility that the two genes belong to the same genetic pathway, even if Blimp1 function is required in the epithelium whereas Hoxd3 gene expression is restricted to mesenchymal cells ( 22 – 24 ). The importance of Hoxd genes for the patterning of gut mesenchyme derivatives, such as sphincters ( 25 , 26 ), has been well documented.…”

Decoding the differentiation of mesenchymal stem cells into mesangial cells at the transcriptomic level

“…TAGLN in the kidney is up-regulated in repopulating mesangial cells in vivo. Meanwhile SERPINE2 and IGFBP5 are reported to be expressed in mesangial cells [25,26] and MYOM1 is known to be expressed in smooth muscle cells [27].…”