RESUMEN
The DNA damage sensor XPC is involved in nucleotide excision repair. Here we show that in the absence of damage, XPC co-localizes with RNA polymerase II (Pol II) and active post-translational histone modifications marks on a subset of class II promoters in human fibroblasts. XPC depletion triggers specific gene down-expression due to a drop in the deposition of histone H3K9 acetylation mark and pre-initiation complex formation. XPC interacts with the histone acetyltransferase KAT2A and specifically triggers the recruitment of the KAT2A-containing ATAC complex to the promoters of down-expressed genes. We show that a strong E2F1 signature characterizes the XPC/KAT2A-bound promoters and that XPC interacts with E2F1 and promotes its binding to its DNA element. Our data reveal that the DNA repair factor XPC is also an RNA polymerase II cofactor recruiting the ATAC coactivator complex to promoters by interacting with the DNA binding transcription factor E2F1.
Asunto(s)
Proteínas de Unión al ADN/genética , Factor de Transcripción E2F1/genética , Histona Acetiltransferasas/genética , Histonas/genética , Procesamiento Proteico-Postraduccional , ARN Polimerasa II/genética , Acetilación , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Factor de Transcripción E2F1/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Células HeLa , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Humanos , Cultivo Primario de Células , Regiones Promotoras Genéticas , Unión Proteica , ARN Polimerasa II/metabolismo , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/metabolismo , Xerodermia Pigmentosa/patologíaRESUMEN
Since small-animal MRI generally requires anesthesia, the effect of the anesthetic regimen on the explored organ(s) has to be taken into account for study interpretation. In this work, we assess the influence of ketamine/xylazine and isoflurane anesthesia on left-ventricular (LV) function in the mouse in vivo by cine-MRI. Three groups of animals were anesthetized with ketamine/xylazine (n = 13) and two different concentrations of isoflurane (1.25%, n = 12 and 2.00%, n = 12) delivered in O2/N2O mix. Long- and short-axis cine-MRI was performed to measure end-diastolic volume, stroke volume, ejection fraction and LV wall thickness. Ketamine/xylazine significantly reduced heart rate, cardiac output and wall thickness, but increased stroke volume and end-diastolic volume compared with both isoflurane groups. No differences across all groups were observed in ejection fraction or systolic wall thickening. Breath rate under isoflurane was significantly lower and concentration dependent, whereas heart function was independent of concentration in all measured parameters. These findings are in agreement with echocardiography and catheterization studies. Isoflurane is advantageous for MR studies because it better maintains cardiac function. Taking into account previously obtained myocardial perfusion measurements, isoflurane concentration should, however, be maintained at the minimum required for a stable sleep even if cardiac function is unaffected by higher isoflurane concentrations.
