Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, M5S3G5, Canada.
Department of Biology, University of Toronto, Mississauga, Ontario, L5L1C6, Canada.
Nat Commun. 2022 May 18;13(1):2733. doi: 10.1038/s41467-022-30192-z.
Mammalian genomes comprise largely intergenic noncoding DNA with numerous cis-regulatory elements. Whether and how the size of intergenic DNA affects gene expression in a tissue-specific manner remain unknown. Here we show that genes with extended intergenic regions are preferentially expressed in neural tissues but repressed in other tissues in mice and humans. Extended intergenic regions contain twice as many active enhancers in neural tissues compared to other tissues. Neural genes with extended intergenic regions are globally co-expressed with neighboring neural genes controlled by distinct enhancers in the shared intergenic regions. Moreover, generic neural genes expressed in multiple tissues have significantly longer intergenic regions than neural genes expressed in fewer tissues. The intergenic regions of the generic neural genes have many tissue-specific active enhancers containing distinct transcription factor binding sites specific to each neural tissue. We also show that genes with extended intergenic regions are enriched for neural genes only in vertebrates. The expansion of intergenic regions may reflect the regulatory complexity of tissue-type-specific gene expression in the nervous system.
哺乳动物基因组主要由基因间非编码 DNA 组成，其中包含大量顺式调控元件。基因间 DNA 的大小是否以及如何以组织特异性的方式影响基因表达仍然未知。在这里，我们发现在小鼠和人类中，具有扩展基因间区域的基因在神经组织中优先表达，而在其他组织中受到抑制。与其他组织相比，神经组织中的扩展基因间区域包含两倍数量的活跃增强子。具有扩展基因间区域的神经基因与由共享基因间区域中不同增强子控制的邻近神经基因整体上具有共表达关系。此外，在多种组织中表达的通用神经基因的基因间区域明显长于在较少组织中表达的神经基因。通用神经基因的基因间区域具有许多组织特异性的活跃增强子，其中包含每个神经组织特有的不同转录因子结合位点。我们还表明，只有脊椎动物中基因间区域扩展的基因富集了神经基因。基因间区域的扩展可能反映了神经系统中组织类型特异性基因表达的调控复杂性。
