Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting the deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that affected large gene clusters. In the brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3), and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.

• MeSH
• DNA MeSH
• jaderné proteiny * metabolismus   MeSH
• metylace DNA MeSH
• myši MeSH
• protein - isoformy genetika   MeSH
• proteiny buněčného cyklu * metabolismus   MeSH
• represorové proteiny genetika   MeSH
• transkripční faktory genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In mice, the entry of germ cells into meiosis crucially depends on the expression of stimulated by retinoic acid gene 8 (Stra8). Stra8 is expressed specifically in pre-meiotic germ cells of females and males, at fetal and postnatal stages, respectively, but the mechanistic details of its spatiotemporal regulation are yet to be defined. In particular, there has been considerable debate regarding whether retinoic acid is required, in vivo, to initiate Stra8 expression in the mouse fetal ovary. We show that the distinctive anterior-to-posterior pattern of Stra8 initiation, characteristic of germ cells in the fetal ovary, is faithfully recapitulated when 2.9 kb of the Stra8 promoter is used to drive eGFP expression. Using in vitro transfection assays of cutdown and mutant constructs, we identified two functional retinoic acid responsive elements (RAREs) within this 2.9 kb regulatory element. We also show that the transcription factor DMRT1 enhances Stra8 expression, but only in the presence of RA and the most proximal RARE. Finally, we used CRISPR/Cas9-mediated targeted mutation studies to demonstrate that both RAREs are required for optimal Stra8 expression levels in vivo.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• CRISPR-Cas systémy genetika   MeSH
• meióza MeSH
• mutageneze MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• ovarium cytologie   metabolismus   MeSH
• plod cytologie   metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese účinky léků   MeSH
• regulační oblasti nukleových kyselin genetika   MeSH
• retinoidní X receptory genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   farmakologie   MeSH
• tretinoin farmakologie   MeSH
• vazebná místa MeSH
• vývoj plodu genetika   MeSH
• zárodečné buňky cytologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The Cdx2 homeobox gene is important in assigning positional identity during the finely orchestrated process of embryogenesis. In adults, regenerative responses to tissues damage can require a replay of these same developmental pathways. Errors in reassigning positional identity during regeneration can cause metaplasias-normal tissue arising in an abnormal location-and this in turn, is a well-recognized cancer risk factor. In animal models, a gain of Cdx2 function can elicit a posterior shift in tissue identity, modeling intestinal-type metaplasias of the esophagus (Barrett's esophagus) and stomach. Conversely, loss of Cdx2 function can elicit an anterior shift in tissue identity, inducing serrated-type lesions expressing gastric markers in the colon. These metaplasias are major risk factors for the later development of esophageal, stomach and colon cancer. Leukemia, another cancer in which Cdx2 is ectopically expressed, may have mechanistic parallels with epithelial cancers in terms of stress-induced reprogramming. This review will address how animal models have refined our understanding of the role of Cdx2 in these common human cancers.

• MeSH
• ezofágus patologie   MeSH
• homeoboxové geny genetika   MeSH
• kolon patologie   MeSH
• lidé MeSH
• metaplazie genetika   patologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory jícnu genetika   patologie   MeSH
• nádory tračníku genetika   patologie   MeSH
• nádory žaludku genetika   patologie   MeSH
• progrese nemoci MeSH
• regulace genové exprese u nádorů * MeSH
• transkripční faktor CDX2 genetika   metabolismus   MeSH
• žaludek patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid proliferation and extensive epigenetic programming. Here we show that Fam208a, a new epigenetic modifier, is essential for early post-implantation development. We show that Fam208a mutation leads to impaired primitive streak elongation and delayed epithelial-to-mesenchymal transition. Fam208a mutant epiblasts had increased expression of p53 pathway genes as well as several pluripotency-associated long non-coding RNAs. Fam208a mutants exhibited an increase in p53-driven apoptosis and complete removal of p53 could partially rescue their gastrulation block. This data demonstrates a new in vivo function of Fam208a in maintaining epiblast fitness, establishing it as an important factor at the onset of gastrulation when cells are exiting pluripotency.

• MeSH
• apoptóza MeSH
• epigeneze genetická * MeSH
• epitelo-mezenchymální tranzice MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• mutace MeSH
• myši MeSH
• primitivní proužek embryologie   MeSH
• zárodečné listy embryologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

TMEM70, a 21-kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encephalo-cardiomyopathy (OMIM 604273). To better understand the biological role of this factor, we generated Tmem70-deficient mice and found that the homozygous Tmem70-/- knockouts exhibited profound growth retardation and embryonic lethality at ∼9.5 days post coitum. Blue-Native electrophoresis demonstrated an isolated deficiency in fully assembled ATP synthase in the Tmem70-/- embryos (80% decrease) and a marked accumulation of F1 complexes indicative of impairment in ATP synthase biogenesis that was stalled at the early stage, following the formation of F1 oligomer. Consequently, a decrease in ADP-stimulated State 3 respiration, respiratory control ratio and ATP/ADP ratios, indicated compromised mitochondrial ATP production. Tmem70-/- embryos exhibited delayed development of the cardiovascular system and a disturbed heart mitochondrial ultrastructure, with concentric or irregular cristae structures. Tmem70+/- heterozygous mice were fully viable and displayed normal postnatal growth and development of the mitochondrial oxidative phosphorylation system. Nevertheless, they presented with mild deterioration of heart function. Our results demonstrated that Tmem70 knockout in the mouse results in embryonic lethality due to the lack of ATP synthase and impairment of mitochondrial energy provision. This is analogous to TMEM70 dysfunction in humans and verifies the crucial role of this factor in the biosynthesis and assembly of mammalian ATP synthase.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• homozygot MeSH
• kardiomyopatie metabolismus   MeSH
• membránové proteiny nedostatek   genetika   metabolismus   MeSH
• mitochondriální membrány metabolismus   MeSH
• mitochondriální nemoci genetika   metabolismus   MeSH
• mitochondriální proteiny nedostatek   genetika   metabolismus   MeSH
• mitochondriální protonové ATPasy biosyntéza   genetika   metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• mutace MeSH
• myši knockoutované MeSH
• myši MeSH
• oxidativní fosforylace MeSH
• těhotenství MeSH
• vrozené poruchy metabolismu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH