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RNA sequencing differential expression and small RNA analyses of obesity and BMI with post-mortem human brain

Obesity, the accumulation of body fat to excess, may cause serious negative health effects including increased risk of heart disease, type 2 diabetes, stroke and certain cancers. RNA sequencing studies in the human brain related to obesity have not been previously undertaken. I conducted both large and small RNA sequencing of hypothalamus (207 samples) and nucleus accumbens (276 samples) from individuals defined as consistently obese (124 samples), consistently normal weight as controls (148 samples) or selected without respect to BMI and falling within neither case nor control definition (211 samples), based on longitudinal BMI measures. The samples were provided by three cohort studies with brain donation programs; the Framingham Heart Study, the Religious Orders Study and the Memory Aging Project. For each brain region and large/small RNA sequencing set, differential expression of obesity, BMI, brain region and sex was performed. There are sixteen mRNAs and five microRNAs that are differentially expressed (adjusted p < 0:05) by obesity or BMI in these tissues. Some genes, such as APOBR and CES1 and some gene sets, such as Reactome’s “opioid signaling”, yielded findings with interesting implications.

The small RNA sequencing data was used for novel analyses of microRNAs (miRNAs), discovering novel miRNAs and characterizing post-transcriptionally edited miRNAs (isomiRs). A custom miRNA identification analysis pipeline was built, which utilizes miRDeep* miRNA identification and result filtering based on false positive rate estimates. With this analysis I discovered over 300 novel miRNAs. Our isomiR analysis included isomiR-specific read filtering based on genome-alignment, and generated a set of isomiR reads which show editing patterns that are non-random with respect to the position and nucleotide of the edit. Specifically, purine substitution, pyrimidine substitution and 3’ polyadenylation and polyuridylation are commonly observed. The patterns of editing revealed that some miRNAs are almost always edited while others are very rarely. I developed a novel statistical test to determine differences in the isomiR profiles of individual miRNAs between two sets of samples. This method revealed 58 miRNAs with differentially edited isomiRs between the two brain regions, but none when comparing obese with control samples or male with female samples.
Date29 September 2019
CreatorsWake, Christian
ContributorsDeStefano, Anita, Myers, Richard
Source SetsBoston University
Detected LanguageEnglish

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