The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice

Abstract

Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis.

Conjugated activation of myocardial-specific transcription of Gja5 by a pair of Nkx2-5-Shox2 co-responsive elements

“…All these three sites share motif -(C/G)CACT(T/C)-, consistent with our Nkx2-5 ChIP-seq results (Ye et al, 2015) and results from another study (He et al, 2011). Our previous studies showed that Shox2 has distinct binding sites among different tissues during organogenesis (Wang et al, 2020;Ye et al, 2016Ye et al, , 2015, but a common motif is yet to be characterized. The binding preferences of Shox2 may be partially dependent upon other co-factors, such as Hox family transcription factors, as reported previously (Ye et al, 2016).…”

Conjugated activation of myocardial-specific transcription ofGja5by a pair of Nkx2-5-Shox2 co-responsive elements

“…All these three sites share motif -(C/G)CACT(T/C)-, consistent with our Nkx2-5 ChIP-seq results (Ye et al, 2015) and results from another study (He et al, 2011). Our previous studies showed that Shox2 has distinct binding sites among different tissues during organogenesis (Wang et al, 2020;Ye et al, 2016Ye et al, , 2015, but a common motif is yet to be characterized. The binding preferences of Shox2 may be partially dependent upon other co-factors, such as Hox family transcription factors, as reported previously (Ye et al, 2016).…”

Osteogenic and angiogenic profiles of the palatal process of the maxilla and the palatal process of the palatine bone

“…Studies on palatal osteogenesis, however, are quite few and limited (Bush & Jiang, 2012). Osteogenesis is a complicated process, but only early osteoblast differentiation is discussed in current studies (Baek et al, 2011; Pauws et al, 2009; Wang et al, 2020; Xu et al, 2018, 2019). In addition, the investigated periods of early osteoblast differentiation differ in multiple publications, making it difficult to understand hard palate development.…”