Cell Rep. 2021 Apr 13;35(2):108981. doi: 10.1016/j.celrep.2021.108981. PMID: 33852861.
Mutations in the promotor region of the insulin gene are associated with a subtype of neonatal diabetes mellitus (NDM). These mutations lead to abnormal transcription of the insulin gene and do so by deleting the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements of the gene. The promoter mutations are highly informative because they provide human genetic evidence that discrete insulin gene cis regulatory elements are essential. In cultured cells, the activity of these cis regulatory elements seems important but it is not known if each of these cis elements is required in-vivo to activate insulin gene transcription. So, to address this question, the authors inserted the human insulin gene regulatory region into a non-coding region of the mouse insulin gene and used this to study how the common promotor mutation (c.-331C > G, CC nucleotide) in the insulin gene leads to NDM.
The study has two important findings. First, this mutation leads to disruption of active chromatin formation during the development of the pancreas so that transcription is repressed. Secondly, an important transcription factor (called GLIS3, which also causes NDM when disrupted) was required to activate insulin gene chromatin and the insulin gene transcription in-vivo. The CC element in the promotor region of the insulin genes acts as an essential seeding site to allow chromatin opening and transcriptional activation of the insulin promotor during beta-cell development. The c.-331C > G mutation prevented GLIS3 activation of both chromatin and insulin gene transcription.