A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

Joglekar, Anoushka; Prjibelski, Andrey D.; Mahfouz, Ahmed; Collier, Paul; Lin, Susan; Schlusche, Anna Katharina; Marrocco, Jordan; Williams, Stephen R.; Haase, Bettina; Hayes, Ashley; Chew, Jennifer; Weisenfeld, Neil; Wong, Man Ying; Stein, Alexander N.; Hardwick, Simon A.; Hunt, Toby; Wang, Qi; Dieterich, Christoph; Bent, Zachary; Fédrigo, Olivier; Sloan, Steven A.; Risso, Davide; Jarvis, Erich D.; Flicek, Paul; Luo, Wenjie; Pitt, Geoffrey S.; Frankish, Adam; Smit, August B.; Ross, M. Elizabeth; Tilgner, Hagen

doi:10.1038/s41467-020-20343-5

Cited by 151 publications

(172 citation statements)

References 88 publications

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“…A similar underestimation of hybrid exons is true when conditioning on annotated exons and comparing to HIT index classifications (Figure 3D). Consistent with previous work (28), we find that only a minority of annotated exons are expressed in a single cell type and of these, many hybrid exons are mis-classified as internal exons. Together, our new classifications show that a reliance on genome annotations in RNA-seq analyses underestimates the usage of alternative terminal exons by mis-classifying hybrid exons.…”

Section: Resultssupporting

confidence: 92%

Widespread occurrence of hybrid internal-terminal exons in human transcriptomes

Fiszbein

McGurk

Calvo-Roitberg

et al. 2021

Preprint

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Alternative RNA processing is a major mechanism for diversifying the human transcriptome. Messenger RNA isoform differences are predominantly driven by alternative first exons, cassette internal exons and alternative last exons. Despite the importance of classifying exons to understand isoform structure, there is a lack of tools to look at isoform-specific exon usage using RNA-sequencing data. We recently observed that alternative transcription start sites often arise near annotated internal exons, creating hybrid exons that can be used as both first or internal exons. To investigate the creation of hybrid exons, we built the HIT (Hybrid-Internal-Terminal) exon pipeline that systematically classifies exons depending on their isoform-specific usage. Using a combination of junction reads coverage and probabilistic modeling, the HIT index identified thousands of hybrid first-internal and internal-last exons that were previously misclassified. Hybrid exons are enriched in long genes with at least ten internal exons, have longer flanking introns and strong splice sites. The usage of hybrid exons varies considerably across human tissues, but they are predominantly used in brain, testis and colon cells. Notably, genes involved in RNA splicing have the highest fraction of intra-tissue hybrid exons. Further, we found more than 100,000 inter-tissue hybrid exons that changed from internal to terminal exons across tissues. By developing the first method that can classify exons according to their isoform contexts, our findings demonstrate the existence of hybrid exons, expand the repertoire of tissue-specific terminal exons and uncover unexpected complexities of the human transcriptome.

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Section: Resultssupporting

confidence: 92%

Widespread occurrence of hybrid internal-terminal exons in human transcriptomes

Fiszbein

McGurk

Calvo-Roitberg

et al. 2021

Preprint

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“…The hippocampus has cell- and compartment-specific transcriptomes, as it is divided into 4 major subregions (CA1, CA2, CA3, and the dentate gyrus) with diverse gene expression schemes to control subregion-specific properties and functions (Masser et al, 2014 ; Cembrowski et al, 2016 ; Farris et al, 2019 ). Several studies have identified alternative splicing programs that readily distinguish neuron cell classes (glutamatergic, GABAergic, glia; Zhang et al, 2014 ; Furlanis et al, 2019 ; Sapkota et al, 2019 ; Feng et al, 2021 ; Joglekar et al, 2021 ) and to a lesser extent distinguish neuron subclasses (CA1, CA3; Furlanis et al, 2019 ; Joglekar et al, 2021 ), indicating that alternate isoform expression is a driver of functional specification (Furlanis et al, 2019 ). Cell-specific expression of transcription factors and epigenetic modifiers likely induce expression of these specialized transcriptomes, but it is still unknown how they communicate with the splicing machinery to induce expression of one isoform over another.…”

Section: Are There Subregion-specific Splicing Programs In the Hippocampus?mentioning

confidence: 99%

“…Alternative isoform expression is one regulatory mechanism well poised to mediate spatial and temporal gene expression in neurons. Alternative isoform expression results from the interplay of many different RNA regulatory processes, including alternative promoter usage (alternative first exon; Twine et al, 2013 ), alternative exon splicing (Ha et al, 2021 ; Joglekar et al, 2021 ), alternative last exon usage (Taliaferro et al, 2016 ), and alternative polyadenylation (APA; Fontes et al, 2017 ; Ha et al, 2021 ; Figure 1 ). This coordinated inclusion or exclusion of specific cis RNA sequences can determine the spatiotemporal expression profile of a given transcript via differential binding of trans -acting factors.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Regulation of Transcript Isoform Expression in the Hippocampus

Park

Farris

2021

Front. Mol. Neurosci.

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Proper development and plasticity of hippocampal neurons require specific RNA isoforms to be expressed in the right place at the right time. Precise spatiotemporal transcript regulation requires the incorporation of essential regulatory RNA sequences into expressed isoforms. In this review, we describe several RNA processing strategies utilized by hippocampal neurons to regulate the spatiotemporal expression of genes critical to development and plasticity. The works described here demonstrate how the hippocampus is an ideal investigative model for uncovering alternate isoform-specific mechanisms that restrict the expression of transcripts in space and time.

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“…Higher order brain functions, and those functions critical to sustain life are facilitated by the concerted activity of different cell types, each functionally driven by distinct, context dependent gene expression and gene expression regulation patterns ( Hawrylycz et al, 2012 ; Mitra et al, 2021 ). Recently, the application of single cell RNA-sequencing technologies has begun to reveal at single cell resolution this dynamic and distinct gene expression patterns and how they respond to stimulus or activity ( Agarwal et al, 2020 ; Pfisterer et al, 2020 ; Joglekar et al, 2021 ; Song et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

Mathoux¹,

Henshall²,

Brennan³

2021

Front. Cell. Neurosci.

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RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

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A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

Cited by 151 publications

References 88 publications

Widespread occurrence of hybrid internal-terminal exons in human transcriptomes

Widespread occurrence of hybrid internal-terminal exons in human transcriptomes

Spatiotemporal Regulation of Transcript Isoform Expression in the Hippocampus

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

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