It Seems Like Only Yesterday

Richardson, Charles C.

doi:10.1146/annurev-biochem-060614-033850

Cited by 5 publications

(7 citation statements)

References 280 publications

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“…In eukaryotic cells, precursor messenger RNAs (pre-mRNAs) can be extensively modified by a process termed pre-mRNA splicing 10 . During splicing, introns are removed and exons are joined together to generate the mRNA template that carries the code to synthesize proteins.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Lim¹,

Zhou²,

Jeon³

et al. 2020

Nat Commun

128

119

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While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of full-length protein by preventing naturally occurring non-productive alternative splicing and promoting generation of productive mRNA. Bioinformatics analysis of RNA sequencing data identifies non-productive splicing events in 7,757 protein-coding human genes, of which 1,246 are disease-associated. Antisense oligonucleotides targeting multiple types of non-productive splicing events lead to increases in productive mRNA and protein in a dose-dependent manner in vitro. Moreover, intracerebroventricular injection of two antisense oligonucleotides in wild-type mice leads to a dose-dependent increase in productive mRNA and protein in the brain. The targeting of natural non-productive alternative splicing to upregulate expression from wild-type or hypomorphic alleles provides a unique approach to treating genetic diseases.

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Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Lim¹,

Zhou²,

Jeon³

et al. 2020

Nat Commun

128

119

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“…Better access to auditory input and to the development of spoken language has raised doubts about the usefulness of combining linguistic input from signs with spoken language for implanted children (Knoors and Marschark, 2012; Spencer, 2016). A number of studies (McDonald Connor et al, 2000; Geers and Sedey, 2002; Geers et al, 2003; Spencer et al, 2003; Geers, 2006; Spencer and Tomblin, 2006; Miyamoto et al, 2009) have investigated the role of signs in enhancing spoken language development by comparing language skills of children with CIs exposed to spoken language-only in Oral Communication (OC) settings and children enrolled in Total Communication (TC) settings.…”

Section: Introductionmentioning

confidence: 99%

“…Sign-supported speech (SSS), also known as ‘simultaneous communication,’ is a form of TC in which the signed lexicon accompanying spoken language is borrowed from the indigenous sign language, sign markers are minimally used and not every single word is necessarily signed. As far as possible, signs and spoken language are produced simultaneously following the syntax of the spoken language (Spencer, 2016). This is different from natural code-blends produced by bimodal bilinguals, in which either spoken or sign language can be the matrix language that provides the syntactic structure of the sentence (Emmorey et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

An Eye Tracking Study on the Perception and Comprehension of Unimodal and Bimodal Linguistic Inputs by Deaf Adolescents

2017

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An eye tracking experiment explored the gaze behavior of deaf individuals when perceiving language in spoken and sign language only, and in sign-supported speech (SSS). Participants were deaf (n = 25) and hearing (n = 25) Spanish adolescents. Deaf students were prelingually profoundly deaf individuals with cochlear implants (CIs) used by age 5 or earlier, or prelingually profoundly deaf native signers with deaf parents. The effectiveness of SSS has rarely been tested within the same group of children for discourse-level comprehension. Here, video-recorded texts, including spatial descriptions, were alternately transmitted in spoken language, sign language and SSS. The capacity of these communicative systems to equalize comprehension in deaf participants with that of spoken language in hearing participants was tested. Within-group analyses of deaf participants tested if the bimodal linguistic input of SSS favored discourse comprehension compared to unimodal languages. Deaf participants with CIs achieved equal comprehension to hearing controls in all communicative systems while deaf native signers with no CIs achieved equal comprehension to hearing participants if tested in their native sign language. Comprehension of SSS was not increased compared to spoken language, even when spatial information was communicated. Eye movements of deaf and hearing participants were tracked and data of dwell times spent looking at the face or body area of the sign model were analyzed. Within-group analyses focused on differences between native and non-native signers. Dwell times of hearing participants were equally distributed across upper and lower areas of the face while deaf participants mainly looked at the mouth area; this could enable information to be obtained from mouthings in sign language and from lip-reading in SSS and spoken language. Few fixations were directed toward the signs, although these were more frequent when spatial language was transmitted. Both native and non-native signers looked mainly at the face when perceiving sign language, although non-native signers looked significantly more at the body than native signers. This distribution of gaze fixations suggested that deaf individuals – particularly native signers – mainly perceived signs through peripheral vision.

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“…Alternative splicing is a highly regulated process by the activities of trans -acting splicing regulators. These splicing regulators include the serine- and arginine-rich splicing factors (SRSFs) and the heterogeneous nuclear ribonucleoproteins (hnRNPs) that bind to cis -regulatory sequences in the pre-mRNA to modify splicing (20). To identify splicing factors that modify exon 2 splicing, we systematically knocked down the expression of known SRSFs and hnRNPs in a cell-based small interfering RNA (siRNA) screen.…”

Section: Resultsmentioning

confidence: 99%

“…In general, control of alternative splicing events is mediated by trans -acting splicing regulators that bind to cis -regulatory sequences within or near the regulated exon. Splicing factors that bind to the pre-mRNA act bidirectionally to enhance or silence splicing based on (i) the properties of the protein, (ii) the binding location relative to the alternatively spliced exon, and (iii) whether it cooperates or competes with other splicing enhancers or silencers that may function in the same region (20).…”

Section: Introductionmentioning

confidence: 99%

SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer’s Disease Risk

Bergeijk

Seneviratne

Aparicio-Prat

et al. 2019

Molecular and Cellular Biology

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A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer’s disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3′ end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33’s regulation of microglial signaling underpinning the AD genetic associations.

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It Seems Like Only Yesterday

Cited by 5 publications

References 280 publications

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

An Eye Tracking Study on the Perception and Comprehension of Unimodal and Bimodal Linguistic Inputs by Deaf Adolescents

SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer’s Disease Risk

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