Extended intergenic DNA contributes to neuron-specific expression of neighboring genes in the mammalian nervous system

A large part of noncoding DNA is intergenic regions, yet how the size of intergenic regions affects gene expression in a tissue-specific manner is unclear. Here the authors present long intergenic DNA length-dependent neural gene expression, reflecting the complexity in the mammalian nervous system. 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.

Automated summary

This study reveals that extended intergenic regions play a role in tissue-specific gene expression, particularly in neural tissues. These intergenic regions contain more active enhancers and are associated with co-expression of neighboring neural genes. Generic neural genes expressed in multiple tissues have longer intergenic regions and contain tissue-specific enhancers.