Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution

Abstract

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain in precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of new lncRNAs have appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. LncRNAs are increasingly reported to be involved in neurodevelopmental processes including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity, suggested to underlie human brain evolution. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review.

Neuronal Lhx1 expression is regulated by DNMT1-dependent modulation of histone marks

“…Moreover, we identified numerous transcripts related to histone acetylation and deacetylation that were altered in expression in Dnmt1-deficient POA cells, indicating multiple levels of regulation. Besides, other mechanisms that would enable a crosstalk between DNMT1 and histone acetylation, for example, via transcriptional control over long non-coding RNA expression that in turn can recruit or avoid the binding of chromatin-modifying complexes [68], or an interaction of DNMT1 with the histone acetylation machinery at protein level similar to what we identified for the DNMT1-dependent establishment of H3K27me3 marks [12], are likewise conceivable and subject of further investigations.…”

DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes

“…Moreover, certain histone modifications can prevent or promote DNA methylation [ 74 ], whereby DNMT1 function could be secondarily affected by mutant HTT-induced changes of the histone code. Non-coding RNAs (ncRNAs) likewise exert transcriptional control in part by recruiting or preventing the binding of proteins/complexes involved in setting up DNA methylation and histone modification marks [ 75 ]. Mutant HTT modulates REST function, which controls the expression of diverse long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), several of which are found dysregulated in HD [ 76 ].…”

“…Hence, DNMT1 function and DNA methylation targeting could be affected by the altered repertoire of ncRNAs. lncRNAs with critical functions in neuronal development [ 75 ] are known to regulate the binding of DNMTs to the DNA, thereby being involved in mediating site-specific methylation [ 77 , 78 ].…”

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons

“…Epigenetic mechanisms involve inheritable as well as reversible chromatin modifications, including DNA methylation and histone modifications, which influence gene transcription and post-transcriptional events ( Fuks, 2005 ). Further epigenetic key players are represented by non-coding RNAs, which can act on transcriptional, post-transcriptional, and translational level ( Geisler and Coller, 2013 ; Cech and Steitz, 2014 ; Zimmer-Bensch, 2019b ).…”