Two New Members of the Murine Sim Gene Family Are Transcriptional Repressors and Show Different Expression Patterns during Mouse Embryogenesis

Abstract

From a cDNA library of mouse skeletal muscle, we have isolated mouse Sim1 (mSim1) cDNA encoding a polypeptide of 765 amino acids with striking amino acid identity in basic helix-loop-helix (89% identity) and PAS (89% identity) domains to previously identified mSim2, although the carboxy-terminal third of the molecule did not show any similarity to mSim2 or Drosophila Sim (dSim). Whole-mount in situ hybridization showed restricted and characteristic expression patterns of the two mSim mRNAs in various tissues and organs during embryogenesis, such as those for the somite, the nephrogenic cord, and the mesencephalon (for mSim1) and those for the diencephalon, branchial arches, and limbs (for mSim2). From sequence similarity and chromosomal localization, it is concluded that mSim2 is an ortholog of hSIM2, which is proposed to be a candidate gene responsible for Down's syndrome. The sites of mSim2 expression showed an overlap with the affected regions of the syndrome, further strengthening involvement of mSim2 in Down's syndrome.

Regulated Transcription of Human Matrix Metalloproteinase 13 (MMP13) and Interleukin-1β (IL1B) Genes in Chondrocytes Depends on Methylation of Specific Proximal Promoter CpG Sites

“…4D), a non-canonical "E-box-like" sequence (CANNTG), to which several bHLH-PAS family transcription factors can bind. A heterodimer of two bHLH-PAS family members, Sim2 and ARNT, binds to non-canonical E-boxes, repressing (62,63) or activating (64) transcription depending upon the promoter and cellular contexts. However, overexpression of Sim2 and ARNT repressed IL1B promoter activity independent of CpG methylation status.…”

Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene

“…Later, Sim2 mRNA expression is also evident at the midline of the caudal diencephalon (mammillary area of the hypothalamus), zona limitans intrathalamica, anterior hypothalamic nuclei, cortex, and olfactory bulb. Areas of mRNA expression outside the CNS include the pharyngeal arches and their later derivatives such as the palate, oral epithelia, tongue epithelia, mandibular and hyoid bones, as well as expression in the vertebrae, rib primordia, some skeletal muscles, lung, and kidney tubules (Ema et al, 1996;Fan et al, 1996). The extent of functional overlap between Sim1 and Sim2 is not known; however, their mRNA expression patterns overlap, especially in the developing CNS (Fan et al, 1996).…”

“…In general, bHLH-PAS family members heterodimerize to form transcriptional activators, an activity mediated through C-terminal domains (Franks and Crews, 1994;Jain et al, 1994). Sim1 and Sim2 may differ in this regard, as heterodimers between either protein and the aryl hydrocarbon receptor nuclear translocator (ARNT) have been shown to be transcriptional repressors in human embryonic kidney and COS-7 cell culture systems (Ema et al, 1996;Moffett et al, 1997). The human SIM2 gene maps to chromosome 21q22.2 and, therefore, may play a role in the features of Down syndrome when overexpressed.…”

“…Sim1, a second mammalian homologue of sim, shares a high degree of sequence identity with Sim2 in the N-terminal bHLH and PAS dimerization domains (Ema et al, 1996;Fan et al, 1996). In general, bHLH-PAS family members heterodimerize to form transcriptional activators, an activity mediated through C-terminal domains (Franks and Crews, 1994;Jain et al, 1994).…”

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

“…Most of the current understanding of SIM2/ARNT transcriptional activities comes from studies of the mSIM2 long isoform. Cell-based reporter gene assays have shown the murine long isoform to mediate repression of transcription via carboxy-terminal repression domains (Ema et al, 1996b;Moffett et al, 1997;Woods and Whitelaw, 2002). Recently, hSIM2s-mediated repression of the SLUG gene in breast cancer cells has been reported (Laffin et al, 2008).…”