GRHL2 maintains the epithelial state of ovarian cancer cells by
activating expression of the miR-200 family, which in turn inhibits
expression of ZEB1 [67].
These studies raise the question of how GRHL TFs can mediate
both repression and activation of its various gene targets. Genomewide analysis of Grh binding during Drosophila development
revealed that Grh stably bound DNA of target genes, whereas
activation of Grh-target genes was dynamic, suggesting a permissive role for Grh [68]. Recently, Grh was revealed to be a pioneer
factor, able to bind to nucleosomal DNA and induce remodeling of
epithelial gene enhancers to increase chromatin accessibility. Grh
binding is not sufficient to activate gene expression, but instead
primes genes to be activated or repressed by other factors, a function conserved by human GRHL1, 2, and 3 within mammary
epithelial cells [29]. Interestingly, different GRHL family members
have both common and distinct target genes despite high amino
acid sequence similarity and identical DNA consensus sequences
[69]; distinct transcriptional co-regulator binding partners may
thus determine specificity, although this aspect of target gene regulation by GRHL TFs is poorly understood.
5.2 Ovo-Like Family
The zinc-finger Ovo-like (OVOL) family of transcriptional repressors has emerging roles as guardian of the epithelial phenotype.
During mammary morphogenesis in mice, in which TEB cells
undergo transient partial-EMT, TEB-specific loss of OVOL2
leads to increased cell invasion and ductal dysmorphia and impaired
restoration of epithelial characteristics [70]. OVOL2 directly
represses several EMT-inducing TFs including ZEB1, Snail, and
Twist1, and represses expression of the mesenchymal marker
vimentin [70]. Similarly, in the epidermal epithelium in mice, targeted OVOL1/2 double mutations lead to hyperproliferation and
EMT of basal epidermal cells, together with induction of ZEB1,
Slug, and vimentin [71]. Moreover, these changes are partially
inhibited by concomitant deletion of ZEB1, suggesting that
OVOL1/2 represses ZEB1 to establish the epithelial phenotype
in epidermis. OVOL2 binds to and represses ZEB1/2 to maintain
epithelial genes in corneal epithelial cells [72], and targeted disruptions in the ovo1 gene in mice cause defects in kidney and urogenital
system, organs in which MET is critical during development
[73]. At the chromatin level, OVOL1 represses transcription by
recruiting HDAC1 to induce remodeling at target loci [74]. In
turn, ZEB1 can directly bind and repress the OVOL2 promoter,
indicating a ZEB1-OVOL2 mutual inhibitory circuit [75], and
OVOL1 can bind and repress its own promoter, indicating negative
feedback [74], providing mechanisms by which expression of
OVOL1/2 can be tuned to exert spatio-temporal control of EMT.
Mechanisms of MET in Development and Cancer
51
activating expression of the miR-200 family, which in turn inhibits
expression of ZEB1 [67].
These studies raise the question of how GRHL TFs can mediate
both repression and activation of its various gene targets. Genomewide analysis of Grh binding during Drosophila development
revealed that Grh stably bound DNA of target genes, whereas
activation of Grh-target genes was dynamic, suggesting a permissive role for Grh [68]. Recently, Grh was revealed to be a pioneer
factor, able to bind to nucleosomal DNA and induce remodeling of
epithelial gene enhancers to increase chromatin accessibility. Grh
binding is not sufficient to activate gene expression, but instead
primes genes to be activated or repressed by other factors, a function conserved by human GRHL1, 2, and 3 within mammary
epithelial cells [29]. Interestingly, different GRHL family members
have both common and distinct target genes despite high amino
acid sequence similarity and identical DNA consensus sequences
[69]; distinct transcriptional co-regulator binding partners may
thus determine specificity, although this aspect of target gene regulation by GRHL TFs is poorly understood.
5.2 Ovo-Like Family
The zinc-finger Ovo-like (OVOL) family of transcriptional repressors has emerging roles as guardian of the epithelial phenotype.
During mammary morphogenesis in mice, in which TEB cells
undergo transient partial-EMT, TEB-specific loss of OVOL2
leads to increased cell invasion and ductal dysmorphia and impaired
restoration of epithelial characteristics [70]. OVOL2 directly
represses several EMT-inducing TFs including ZEB1, Snail, and
Twist1, and represses expression of the mesenchymal marker
vimentin [70]. Similarly, in the epidermal epithelium in mice, targeted OVOL1/2 double mutations lead to hyperproliferation and
EMT of basal epidermal cells, together with induction of ZEB1,
Slug, and vimentin [71]. Moreover, these changes are partially
inhibited by concomitant deletion of ZEB1, suggesting that
OVOL1/2 represses ZEB1 to establish the epithelial phenotype
in epidermis. OVOL2 binds to and represses ZEB1/2 to maintain
epithelial genes in corneal epithelial cells [72], and targeted disruptions in the ovo1 gene in mice cause defects in kidney and urogenital
system, organs in which MET is critical during development
[73]. At the chromatin level, OVOL1 represses transcription by
recruiting HDAC1 to induce remodeling at target loci [74]. In
turn, ZEB1 can directly bind and repress the OVOL2 promoter,
indicating a ZEB1-OVOL2 mutual inhibitory circuit [75], and
OVOL1 can bind and repress its own promoter, indicating negative
feedback [74], providing mechanisms by which expression of
OVOL1/2 can be tuned to exert spatio-temporal control of EMT.
Mechanisms of MET in Development and Cancer
51