Dysregulation of Regulatory Small Non-Coding RNAs in the Superior Temporal Gyrus Brain Region of Autism Spectrum Disorders
mRNA transcriptomes vary enormously between brain regions. Neocortex transcriptomes are relatively homogeneous with physical proximity correlating with transcriptome similarity. However, transcriptomes of primary sensorimotor cortices are quite distinct from adjacent cortex. Molecular mechanisms responsible for normal regional patterning could involve regulatory RNA, such as small non-coding RNAs (sncRNA) (miRNA, snoRNA), which play fundamental roles in brain development throughout lifespan. Superior temporal gyrus (STG) is a region with importance to neuropsychiatric disorders, including ASD. It consists of two regions, superior temporal sulcus (STS) and primary auditory cortex (PAC), which although adjacent, have different functions. STS is association cortex, involved in social perception, joint attention, interpreting facial gaze and speech inputs, and implicated in ASD. PAC is a primary sensory cortex modulating auditory processing, not associated with ASD.
1) To assess differential regional and age-related expression in STS and PAC in postmortem human brains of TD and ASD. 2) To compare to previous miRNA ASD studies.
Affymetrix miRNA 3.0 arrays were run on 28 samples (8 ASD / 6 TD subjects; 2 brain regions; ages 4-50 years of age). Mixed Regression Models were used to identify regionally differentially expressed genes (p<0.005, |fold-change|>1.2). Spearman Rank correlation was used for age-related expression and co-expression relationships (p<0.005).
We found distinct regional and age-related changes of differentially expressed sncRNAs in TD in STS and PAC, which were significantly attenuated in ASD. This is in line with observations of regional attenuated mRNA expression in ASD brain (Voineagu et al, 2012, Ziats and Rennert, 2012). In addition, because genes function in coordinated networks, to characterize network alterations in ASD, we investigated the co-expression relationships of the age-related miRNAs in TD brains, based on similarity of expression profiles, and compared them to the ones in ASD. In TD, defined positive and negative co-expression clusters were identified, suggesting coordinate expression and/or regulation (Fig. 1). In contrast, ASD brains displayed significant deviations from this coordinated expression, thus potentially dysregulating a large number of downstream mRNA targets (Fig. 1).
We then compared our findings to other miRNA studies in ASD to find gene families with broad dysregulation in ASD (Table 1). Seven miRNA gene families were dysregulated in subsets of ASD cerebellar cortex samples versus non-ASD controls (P of overlap=0.0002) (Table 1, (Abu-Elneel et al., 2008)). Five miRNAs were differentially expressed in lymphoblastoid cell clines (LCL) of affected versus unaffected monozygotic twins discordant for ASD diagnosis/severity (P=0.046) (Table 1, (Sarachana et al., 2010)). Two miRNAs were differentially expressed in LCL between ASD and controls (P=0.047) (Table 1, (Talebizadeh et al., 2008)). One miRNA was differentially expressed in LCL between ASD affected sibs vs unaffected sibs (P=0.413, n.s.) (Table 1, (Ghahramani Seno et al., 2011)). Several of these overlapping miRNAs have fundamental roles in brain development and function.
Conclusions: The combined effects of the differentially expressed sncRNA in ASD brains, likely contribute to aberrant development and function of STS and PAC and may contribute to core ASD symptoms including social dysfunction and communication.