Characterization of SALL2 Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks.
Characterization of SALL2 Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks.
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SALL2基因亚型和靶点在细胞类型中的表征揭示了高度保守的网络。
DOI：
10.3389/fgene.2021.613808
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发表时间：
2021
影响因子：
3.7
通讯作者：
Pincheira R
中科院分区：
文献类型：
--
作者：
Farkas C;Quiroz A;Alvarez C;Hermosilla V;Aylwin CF;Lomniczi A;Castro AF;Hepp MI;Pincheira R
SALL2转录因子是一种在脊椎动物中进化保守的基因，参与正常发育和神经元分化。在疾病中，SALL2与眼睛、肾脏和脑部疾病有关，但主要与癌症有关。一些研究支持SALL2的抑瘤作用，另一些研究支持SALL2的致癌作用，这似乎取决于癌症类型。另一个考虑因素是不同SALL2亚型的组织依赖性表达。人和小鼠SALL2基因位点包含两个启动子，每个启动子控制不同蛋白亚型（E1和E1A）的表达。此外，通过下一代测序技术对人类基因组组装和基因注释进行了改进，揭示了对其他同种异构体的校正和注释，从而模糊了SALL2同种异构体特异性转录靶点和功能的解剖。我们整合了正常/肿瘤基因表达数据库的当前数据以及ChIP-seq结合谱，分析了SALL2亚型的表达分布，并推断了SALL2亚型特异性靶点。我们发现典型的SALL2 E1亚型是表达最低的亚型之一，而E1A亚型在各种细胞类型中都是高度显性的。为了解剖SALL2亚型特异性靶点，我们分析了胶质母细胞瘤肿瘤增殖细胞的公开可用ChIP-seq数据，以及SALL2野生型和E1A亚型敲除HEK293细胞的内部ChIP-seq数据集。我们还分析了过表达非规范SALL2亚型（short_E1A）的HEK293细胞（ENCODE Consortium III期）中另一个可用的ChIP-seq数据。无论细胞类型如何，我们的分析表明，SALL2长E1和E1A亚型，而不是短_e1a亚型，主要参与转录控制，并揭示了一个高度保守的脑特异性转录因子网络（即SALL3， POU3F2和NPAS3）。我们的数据整合鉴定了一个保守的分子网络，其中SALL2调节与神经功能、细胞分化、发育和细胞间粘附相关的基因。此外，我们发现PODXL是一个可能受SALL2跨组织调节的基因。我们的研究鼓励对公开可用的ChIP-seq数据集进行验证，以评估特定基因/异构体的转录靶点。了解SALL2亚型在不同组织环境中的表达和功能，有助于了解其在疾病中的作用。
The SALL2 transcription factor, an evolutionarily conserved gene through vertebrates, is involved in normal development and neuronal differentiation. In disease, SALL2 is associated with eye, kidney, and brain disorders, but mainly is related to cancer. Some studies support a tumor suppressor role and others an oncogenic role for SALL2, which seems to depend on the cancer type. An additional consideration is tissue-dependent expression of different SALL2 isoforms. Human and mouse SALL2 gene loci contain two promoters, each controlling the expression of a different protein isoform (E1 and E1A). Also, several improvements on the human genome assembly and gene annotation through next-generation sequencing technologies reveal correction and annotation of additional isoforms, obscuring dissection of SALL2 isoform-specific transcriptional targets and functions. We here integrated current data of normal/tumor gene expression databases along with ChIP-seq binding profiles to analyze SALL2 isoforms expression distribution and infer isoform-specific SALL2 targets. We found that the canonical SALL2 E1 isoform is one of the lowest expressed, while the E1A isoform is highly predominant across cell types. To dissect SALL2 isoform-specific targets, we analyzed publicly available ChIP-seq data from Glioblastoma tumor-propagating cells and in-house ChIP-seq datasets performed in SALL2 wild-type and E1A isoform knockout HEK293 cells. Another available ChIP-seq data in HEK293 cells (ENCODE Consortium Phase III) overexpressing a non-canonical SALL2 isoform (short_E1A) was also analyzed. Regardless of cell type, our analysis indicates that the SALL2 long E1 and E1A isoforms, but not short_E1A, are mostly contributing to transcriptional control, and reveals a highly conserved network of brain-specific transcription factors (i.e., SALL3, POU3F2, and NPAS3). Our data integration identified a conserved molecular network in which SALL2 regulates genes associated with neural function, cell differentiation, development, and cell adhesion between others. Also, we identified PODXL as a gene that is likely regulated by SALL2 across tissues. Our study encourages the validation of publicly available ChIP-seq datasets to assess a specific gene/isoform’s transcriptional targets. The knowledge of SALL2 isoforms expression and function in different tissue contexts is relevant to understanding its role in disease.