Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation

Alcott, Callison E; Yalamanchili, Hari Krishna; Ji, Ping; Heijden, Meike E van der; Saltzman, Alexander B.; Elrod, Nathan D.; Ai, Lin; Leng, Mei; Bhatt, Bhoomi; Hao, Shuang; Wang, Qi; Saliba, Afaf; Tang, Jianrong; Malovannaya, Anna; Wagner, Eric J.; Liu, Zhandong; Zoghbi, Huda Y.

doi:10.7554/elife.50895

Cited by 29 publications

(32 citation statements)

References 83 publications

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“…Phenotype analysis of PolyA-miner predicted genes with 3′UTR shortening showed enrichment for intellectual disability, neurodevelopmental delays and other neuropsychiatric phenotypes (Figure 3E and Supplementary Table S3 ). These align with the recent advances in NUDT21 biology ( 39 , 40 ). On the other hand, phenotype enrichment of DPU predictions is limited ( Supplementary Figure S7c, Table S4 ).…”

Section: Resultssupporting

confidence: 81%

PolyA-miner: accurate assessment of differential alternative poly-adenylation from 3′Seq data using vector projections and non-negative matrix factorization

Yalamanchili

Alcott

et al. 2020

Nucleic Acids Research

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Abstract Almost 70% of human genes undergo alternative polyadenylation (APA) and generate mRNA transcripts with varying lengths, typically of the 3′ untranslated regions (UTR). APA plays an important role in development and cellular differentiation, and its dysregulation can cause neuropsychiatric diseases and increase cancer severity. Increasing awareness of APA’s role in human health and disease has propelled the development of several 3′ sequencing (3′Seq) techniques that allow for precise identification of APA sites. However, despite the recent data explosion, there are no robust computational tools that are precisely designed to analyze 3′Seq data. Analytical approaches that have been used to analyze these data predominantly use proximal to distal usage. With about 50% of human genes having more than two APA isoforms, current methods fail to capture the entirety of APA changes and do not account for non-proximal to non-distal changes. Addressing these key challenges, this study demonstrates PolyA-miner, an algorithm to accurately detect and assess differential alternative polyadenylation specifically from 3′Seq data. Genes are abstracted as APA matrices, and differential APA usage is inferred using iterative consensus non-negative matrix factorization (NMF) based clustering. PolyA-miner accounts for all non-proximal to non-distal APA switches using vector projections and reflects precise gene-level 3′UTR changes. It can also effectively identify novel APA sites that are otherwise undetected when using reference-based approaches. Evaluation on multiple datasets—first-generation MicroArray Quality Control (MAQC) brain and Universal Human Reference (UHR) PolyA-seq data, recent glioblastoma cell line NUDT21 knockdown Poly(A)-ClickSeq (PAC-seq) data, and our own mouse hippocampal and human stem cell-derived neuron PAC-seq data—strongly supports the value and protocol-independent applicability of PolyA-miner. Strikingly, in the glioblastoma cell line data, PolyA-miner identified more than twice the number of genes with APA changes than initially reported. With the emerging importance of APA in human development and disease, PolyA-miner can significantly improve data analysis and help decode the underlying APA dynamics.

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Section: Resultssupporting

confidence: 81%

PolyA-miner: accurate assessment of differential alternative poly-adenylation from 3′Seq data using vector projections and non-negative matrix factorization

Yalamanchili

Alcott

et al. 2020

Nucleic Acids Research

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“…Only one mutation involving a core polyadenylation protein, NUDT21 (which encodes the 25 kDa subunit of mammalian cleavage factor I), has been implicated in neuropsychiatric disorders resulting in Rett syndrome-like symptoms and intellectual disability ( 13 , 14 ). We did not observe altered expression of Mecp2 — which is frequently associated with Rett syndrome — in our mouse model (not shown), but observed altered sites of polyadenylation in many other neurodevelopmental genes (Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Fragile X Syndrome is caused by expansion of CGG repeats in the 5′ UTR of FMR1 , resulting in loss-of-function of FMRP, an RNA-binding protein that promotes transport of mRNAs to dendrites for protein synthesis at synaptic sites ( 5 , 6 ). Similarly, mutations in mRNA processing genes encoding decapping enzymes ( 7 , 8 ), the polyglutamine binding protein 1 (PQBP1 ( 9 )), spliceosomal proteins ( 10 ), hnRNA-binding proteins ( 11 ), mRNA surveillance proteins ( 12 ) and cleavage and polyadenylation factors ( 13 , 14 ) cause intellectual disabilities. These disorders are associated with changes in the mRNA processing landscape, especially 3′ end cleavage and polyadenylation (C/P), highlighting the importance of RNA processing in controlling neuronal function ( 15–18 ).…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3′ end processing is associated with intellectual disability in humans

Grozdanov

Masoumzadeh

Kalscheuer

et al. 2020

Nucleic Acids Research

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CSTF2 encodes an RNA-binding protein that is essential for mRNA cleavage and polyadenylation (C/P). No disease-associated mutations have been described for this gene. Here, we report a mutation in the RNA recognition motif (RRM) of CSTF2 that changes an aspartic acid at position 50 to alanine (p.D50A), resulting in intellectual disability in male patients. In mice, this mutation was sufficient to alter polyadenylation sites in over 1300 genes critical for brain development. Using a reporter gene assay, we demonstrated that C/P efficiency of CSTF2D50A was lower than wild type. To account for this, we determined that p.D50A changed locations of amino acid side chains altering RNA binding sites in the RRM. The changes modified the electrostatic potential of the RRM leading to a greater affinity for RNA. These results highlight the significance of 3′ end mRNA processing in expression of genes important for brain plasticity and neuronal development.

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“…NUDT21 is a core regulator of APA, which was shown to be involved in neuronal fate determination of pluripotent stem cells 11 . Partial reduction of NUDT21 protein leads to altered APA in hundreds of genes and intellectual disability 30 . Surprisingly, we also found changes in expression of the synaptic adhesion molecule, amyloid beta precursor like protein 1 (APLP1).…”

Section: Examination Of Neuronal Differentiation In the Mouse Olfactomentioning

confidence: 99%

Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

Göpferich

et al. 2020

Preprint

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SUMMARYAutism spectrum disorder (ASD) is a neurodevelopmental disease affecting social behavior. Many of the high-confident ASD risk genes relate to mRNA translation. Specifically, many of these genes are involved in regulation of gene expression for subcellular compartmentalization of proteins1. Cis-regulatory motifs that often localize to 3’- and 5’-untranslated regions (UTRs) offer an additional path for posttranscriptional control of gene expression. Alternative cleavage and polyadenylation (APA) affect 3’UTR length thereby influencing the presence or absence of regulatory elements. However, APA has not yet been addressed in the context of neurodevelopmental disorders. Here we used single cell 3’end sequencing to examine changes in 3’UTRs along the differentiation from neural stem cells (NSCs) to neuroblasts within the adult brain. We identified many APA events in genes involved in neurodevelopment, many of them being high confidence ASD risk genes. Further, analysis of 3’UTR lengths in single cells from ASD and healthy individuals detected longer 3’UTRs in ASD patients. Motif analysis of modulated 3’UTRs in the mouse adult neurogenic lineage and ASD-patients revealed enrichment of the cytoplasmic and polyadenylation element (CPE). This motif is bound by CPE binding protein 4 (CPEB4). In human and mouse data sets we observed co-regulation of CPEB4 and the CPEB-binding synaptic adhesion molecule amyloid beta precursor-like protein 1 (APLP1). We show that mice deficient in APLP1 show aberrant regulation of APA, decreased number of neural stem cells, and autistic-like traits. Our findings indicate that APA is used for control of gene expression along neuronal differentiation and is altered in ASD patients.

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Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation

Cited by 29 publications

References 83 publications

PolyA-miner: accurate assessment of differential alternative poly-adenylation from 3′Seq data using vector projections and non-negative matrix factorization

PolyA-miner: accurate assessment of differential alternative poly-adenylation from 3′Seq data using vector projections and non-negative matrix factorization

A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3′ end processing is associated with intellectual disability in humans

Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

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