Cirino Andrea, Aurigemma Ilaria, Franzese Monica, Lania Gabriella, Righelli Dario, Ferrentino Rosa, Illingworth Elizabeth, Angelini Claudia, Baldini Antonio
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.
Institute of Genetics and Biophysics, National Research Council, Naples, Italy.
Front Cell Dev Biol. 2020 Sep 8;8:571501. doi: 10.3389/fcell.2020.571501. eCollection 2020.
The T-box transcription factor TBX1 has critical roles in the cardiopharyngeal lineage and the gene is haploinsufficient in DiGeorge syndrome, a typical developmental anomaly of the pharyngeal apparatus. Despite almost two decades of research, if and how TBX1 function triggers chromatin remodeling is not known. Here, we explored genome-wide gene expression and chromatin remodeling in two independent cellular models of loss of function, mouse embryonic carcinoma cells P19Cl6, and mouse embryonic stem cells (mESCs). The results of our study revealed that the loss or knockdown of TBX1 caused extensive transcriptional changes, some of which were cell type-specific, some were in common between the two models. However, unexpectedly we observed only limited chromatin changes in both systems. In P19Cl6 cells, differentially accessible regions (DARs) were not enriched in T-BOX binding motifs; in contrast, in mESCs, 34% ( = 47) of all DARs included a T-BOX binding motif and almost all of them gained accessibility in cells. In conclusion, despite a clear transcriptional response of our cell models to loss of TBX1 in early cell differentiation, chromatin changes were relatively modest.
T 盒转录因子 TBX1 在心脏咽系中起关键作用，该基因在 DiGeorge 综合征中表现为单倍剂量不足，DiGeorge 综合征是一种典型的咽器官发育异常。尽管经过了近二十年的研究，但 TBX1 功能是否以及如何触发染色质重塑尚不清楚。在这里，我们在两个独立的功能丧失细胞模型，即小鼠胚胎癌细胞 P19Cl6 和小鼠胚胎干细胞（mESCs）中，探索了全基因组基因表达和染色质重塑情况。我们的研究结果表明，TBX1 的缺失或敲低会导致广泛的转录变化，其中一些是细胞类型特异性的，一些是两个模型共有的。然而，出乎意料的是，我们在两个系统中都仅观察到有限的染色质变化。在 P19Cl6 细胞中，差异可及区域（DARs）并不富含 T 盒结合基序；相反，在 mESCs 中，所有 DARs 的 34%（ = 47）包含一个 T 盒结合基序，并且几乎所有这些基序在 细胞中获得了可及性。总之，尽管我们的细胞模型在早期细胞分化过程中对 TBX1 的缺失有明显的转录反应，但染色质变化相对较小。
