Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis.

The big tau splice isoform resists Alzheimer's-related pathological changes.

In Alzheimer's disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus . However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions.

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.

Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT.

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that is highly expressed in PDAC and is associated with poor prognosis.

NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1.

Purpose: Gliomas and their surrounding microenvironment constantly interact to promote tumorigenicity, yet the underlying posttranscriptional regulatory mechanisms that govern this interplay are poorly understood.

Methods: Utilizing our established PAC-seq approach and PolyAMiner bioinformatic analysis pipeline, we deciphered the NUDT21-mediated differential APA dynamics in glioma cells.

Results: We identified LAMC1 as a critical NUDT21 alternative polyadenylation (APA) target, common in several core glioma-driving signaling pathways.

PolyAMiner-Bulk: A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data.

More than half of human genes exercise alternative polyadenylation (APA) and generate mRNA transcripts with varying 3' untranslated regions (UTR). However, current computational approaches for identifying cleavage and polyadenylation sites (C/PASs) and quantifying 3'UTR length changes from bulk RNA-seq data fail to unravel tissue- and disease-specific APA dynamics. Here, we developed a next-generation bioinformatics algorithm and application, PolyAMiner-Bulk, that utilizes an attention-based machine learning architecture and an improved vector projection-based engine to infer differential APA dynamics accurately.

PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.

PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes.

Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index.

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk.

Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation.

Alternative polyadenylation (APA) regulates gene expression by cleavage and addition of poly(A) sequence at different polyadenylation sites (PAS) in 3'UTR, thus, generating transcript isoforms with different lengths. Cleavage stimulating factor 64 (CstF64) is an APA regulator which plays a role in PAS selection and determines the length of 3'UTR. CstF64 favors the use of proximal PAS, resulting in 3'UTR shortening, which enhances the protein expression by increasing the stability of the target genes.

Emerging roles of alternative cleavage and polyadenylation (APA) in human disease.

In the messenger RNA (mRNA) maturation process, the 3'-end of pre-mRNA is cleaved and a poly(A) sequence is added, this is an important determinant of mRNA stability and its cellular functions. More than 60%-70% of human genes have three or more polyadenylation (APA) sites and can be cleaved at different sites, generating mRNA transcripts of varying lengths. This phenomenon is termed as alternative cleavage and polyadenylation (APA) and it plays role in key biological processes like gene regulation, cell proliferation, senescence, and also in various human diseases.

Application and design considerations for 3'-end sequencing using click-chemistry.

Over the past 15 years, investigations into alternative polyadenylation (APA) and its function in cellular physiology and pathology have greatly expanded due to the emergent appreciation of its key role in driving transcriptomic diversity. This growth has necessitated the development of new technologies capable of monitoring cleavage and polyadenylation events genome-wide. Advancements in approaches include both the creation of computational tools to re-analyze RNA-seq to identify APA events as well as targeted sequencing approaches customized to focus on the 3'-end of mRNA.

Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function.

Integrated analysis of the aging brain transcriptome and proteome in tauopathy.

Background: Tau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes.

Methods: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau) or a mutant form causing frontotemporal dementia (Tau).

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

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.

Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease.

In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components.

Author Correction: Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.

In the version of this article initially published, the Acknowledgements erroneously included a grant number that did not directly support the work in the article. The last sentence of the Acknowledgments should have read, "The authors' laboratories were supported by National Natural Science Foundation of China grants 31671222 and 31571556 (G.D.