Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis

Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts

“…Among genes in deleted CNVs, two of the genes, SATB2 and MEIS2 , which are deleted in eight and five OFC patients (Table 3 ; Supplementary Tables 2, 5, 6), respectively, have been reported as causative for CP and CLP in several human and animal studies (FitzPatrick et al 2003 ; Beaty et al 2006 ; Britanova et al 2006 ; Dobreva et al 2006 ; Erdogan et al 2007 ; Leoyklang et al 2007 ; Crowley et al 2010 ; Johansson et al 2014 ; Rainger et al 2014 ; Louw et al 2015 ). Six additional genes ( THBS1 , TSHZ1 , TTC28 , WHSC1 , WHSC2 and LETM1 ) encompassed by deleted CNVs have been proposed as the potentially causative genes in critical genomic regions for OFC syndromes (Table 3 ; Supplementary Tables 2, 5) (Wright et al 1997 , 1999 ; Stec et al 1998 ; Zollino et al 2000 , 2003 ; Schlickum et al 2004 ; Nishiwaki et al 2006 ; Coré et al 2007 ; Maas et al 2008 ; Dostal et al 2009 ; Heinonen and Maki 2009 ; Davidson et al 2012 ; Shimizu et al 2014 ; Liu et al 2015 ). Furthermore, three candidates in deleted CNVs, FGF2, FRZB and SPRY1 , have been shown to contribute to orofacial development in animal models and to be involved with signaling pathways whose disruption leads to OFCs in human (Table 3 , Supplementary Tables 2, 5) (Hoang et al 1996 ; Lin et al 1997 ; Hoang et al 1998 ; Mansukhani et al 2000 ; Moore et al 2002 ; Ignelzi et al 2003 ; Sasaki et al 2006 ; Szabo-Roger et al 2008 ; Dickinson et al 2009 ; Porntaveetu et al 2010 ; Yang et al 2010 ; Kamel et al 2013 ).…”

“…In addition to the two known OFC causative genes SATB2 and MEIS2 , we identified other 12 genes, nine in deletions ( FGF2 , FRZB, LETM1 , SPRY1, THBS1 , TSHZ1 , TTC28 , WHSC1 , WHSC2 ) and three in duplications ( DGCR6 , TULP4 and MAPK3 ), that have been previously proposed as orofacial development regulators or as potential causative genes for OFCs (Table 3 ; Supplementary Table 5). WHSC1 , WHSC2 (aka NELFA ) and LETM1 have been proposed to be primarily involved in Wolf–Hirschhorn syndrome (OMIM #194190), whose features include OFC in almost half of the cases (Wright et al 1997 , 1999 ; Stec et al 1998 ; Zollino et al 2000 , 2003 ; Schlickum et al 2004 ; Maas et al 2008 ; Shimizu et al 2014 ; Liu et al 2015 ). Among the OFC patients we collected, all three genes were deleted simultaneously in the same patients, two affected by CP and one by CL (Supplementary Tables 3, 6), consistent with the hypothesis that the deletion of all these three genes is required to cause more severe craniofacial features including OFCs.…”

Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

“…The teratogenic reagent, atRA, induces cleft palate and is widely used for the study of palate formation [15]. atRA has been proposed as a model agent not only for the inhibition of palate elevation but also retention of the MEE [4].…”

Nucleic acid methylation and orofacial morphogenesis

“…While no significant change in overall CpG methylation levels was observed between atRA‐treated and control mice, alterations in global DNA methylation and in methylation of CGIs in mice born to mothers over‐exposed to atRA have been reported (Kuriyama et al, ). An overdose of RA was also observed to inhibit palatal mesenchymal cell proliferation which was correlated with a repression of the Whsc1 gene (Liu, Higashihori, Yahiro, & Moriyama, ). Interestingly, Whsc1 knockout mice exhibit CP (Nimura et al, ).…”