Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

Manabe, Takayuki; Katayama, Taiichi; Sato, Naoyuki; Gomi, Fumi; Hitomi, Junichi; Yanagita, Teruyoshi; Kudo, Takashi; Honda, Akira; Mori, Yuichiro; Matsuzaki, Shinsuke; Imaizumi, Kazunori; Mayeda, Akila; Tohyama, Masaya

doi:10.1038/sj.cdd.4401221

Cited by 71 publications

(131 citation statements)

References 42 publications

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“…In addition, the association of these proteins (and/or additional interacting partners) with C-rs3736234 could more directly influence AS by preventing SRSF1 binding to its adjacent cognate site. Indeed, previous reports identified a direct role for HMGA1a in splicing regulation in presenilin-2 transcripts, based upon sequestration of U1 snRNP on a decoy sequence through interaction of HMGA1a with the U1 snRNP protein U1-70K (Manabe et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

Tejedor

Tilgner

Iannone

et al. 2015

RNA

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The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correlate with the risk of cardiovascular disease. Here we use minigenes to recapitulate the effects of two allelic series (Lowand High-Risk) on OLR1 AS and identify one SNP in intron 4 (rs3736234) as the main contributor to the differences in exon 5 inclusion, while the other SNPs in the allelic series attenuate the drastic effects of this key SNP. Bioinformatic, proteomic, mutational and functional high-throughput analyses allowed us to define regulatory sequence motifs and identify SR protein family members (SRSF1, SRSF2) and HMGA1 as factors involved in the regulation of OLR1 AS. Our results suggest that antagonism between SRSF1 and SRSF2/HMGA1, and differential recognition of their regulatory motifs depending on the identity of the rs3736234 polymorphism, influence OLR1 exon 5 inclusion and the efficiency of Ox-LDL uptake, with potential implications for atherosclerosis and coronary disease.

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Section: Discussionmentioning

confidence: 99%

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

Tejedor

Tilgner

Iannone

et al. 2015

RNA

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“…Vectors were constructed as described previously. 3,21 Transfections and stable clones. The pcDNA6/TR vector (Invitrogen) and pRNATin-H1.2 with L3/Lhx8 siRNA-inducible sequences were transfected into ES cells using Targefect F-1 (Targeting Systems).…”

Section: Methodsmentioning

confidence: 99%

“…Immunocytochemical analyses were performed as described previously. 3,21 The primary antibodies used were anti-choline acetyltransferase (ChAT; mouse monoclonal; Chemicon), anti-GABA (rabbit polyclonal; Sigma) and anti-GFP (mouse monoclonal, Molecular Probes Inc.; rabbit polyclonal, Molecular Probes Inc.; goat polyclonal, Rockland).…”

Section: Methodsmentioning

confidence: 99%

L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells

et al. 2007

Self Cite

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1L3/Lhx8 is a member of the LIM-homeobox gene family. Previously, we demonstrated that L3/Lhx8-null mice specifically lacked cholinergic neurons in the basal forebrain. In the present study, we conditionally suppressed L3/Lhx8 function during retinoic acid-induced neural differentiation of a murine embryonic stem (ES) cell line using an L3/Lhx8-targeted small interfering RNA (siRNA) produced by an H1.2 promoter-driven vector. Our culture conditions induced efficient differentiation of the ES cells into neurons and astrocytes, but far less efficient differentiation into oligodendrocytes. Suppression of L3/Lhx8 expression by siRNA led to a dramatic decrease in the number of cells positive for the cholinergic marker ChAT, and overexpression of L3/Lhx8 recovered this effect. However, no significant changes were observed in the number of Tuj1 þ neurons and GABA þ cells. These results strongly suggest that L3/Lhx8 is a key factor in the cholinergic differentiation of murine ES cells and is involved in basal forebrain development.

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“…66 High mobility group A1 a protein (HMGA1a) had been demonstrated as a splicing regulator of PS2, which binds to a specific sequence in exon 5 preceding 5' splice site. 67 Induced expression of HMGA1, observed in the brain of sporadic AD patients, result in aberrant skipping of PSEN2 exon 5, which is caused by an impaired dissociation of U1 snRNP from the 5' splice site. 67,68 Recently, mutations in RBM20 gene have been shown to be associated with human dilated cardiomyopathy (DCM).…”

Section: 61mentioning

confidence: 99%

“…67 Induced expression of HMGA1, observed in the brain of sporadic AD patients, result in aberrant skipping of PSEN2 exon 5, which is caused by an impaired dissociation of U1 snRNP from the 5' splice site. 67,68 Recently, mutations in RBM20 gene have been shown to be associated with human dilated cardiomyopathy (DCM). 69,70 Deep sequencing of the cardiac transcriptome revealed aberrant splicing of the titin gene (TTN).…”

Section: 61mentioning

confidence: 99%

Decoding Abnormal Splicing Code in Human Diseases

Ohno

Rahman

Nasrin

et al. 2015

JIG

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RNA splicing is an intricate process in humans and higher metazoans. Splicing is regulated through multifaceted coordinated factors, such as cis-acting splicing code and RNAbinding splicing trans-factors that associate or compete with ribonucleoproteins (RNPs). Individual cis-acting splicing code and their functional coordination with cognate splicing trans-factors still remain elusive mostgenes, because these code are comprised of highly degenerative short sequence motifs and multiple splicing trans-factors can recognize an identical motif. In addition, a specific splicing motif functions differentially in different genes, which is determined by additional factors such as neighboring sequence context, cell types and association/competition with other splicing trans-factors. Genetic and cellular alterations compromising the fidelity of splicing processes provoke many human diseases. Analyses of abnormal splicing code in human diseases not only uncover the underlying maladies of splicing regulations in pathological conditions, but also allow us to gain insight into splicing mechanisms in physiological conditions. This review introduces accumulating knowledge of numerous modes of splicing aberrations and provides critical information to understand the underlying patho mechanisms of human diseases, which hopefully leads to development of rational therapies.Keywords: alternative splicing, cis-acting splicing code, splicing trans-factor, spliceosome, mutation, aberrant splicing, neurodegenerative diseases, cancers Journal of Investigative Genomics Review Article Open AccessDecoding abnormal splicing code in human diseases site sequences are highly degenerative, which partly compromises appropriate recognition and binding of essential trans-acting factors. As a consequence, multiple auxiliary trans-acting factors need to co-operate to form spliceosome and to favor folding of nuclear premRNA to commit splicing. The assembly of spliceosome is further regulated by auxiliary splicing cis-elements either in a positive or negative manner (Figure 1b). Positively modulating cis-elements are termed as intronic/exonic splicing enhancers (ISEs/ESEs), whereas negatively modulating cis-elements are termed as intronic/exonic splicing silencers (ISSs/ESSs). Most of these auxiliary cis-elements function by binding to cognate trans-factors (Table 1), whereas some cis-elements function by forming secondary structures. The majority of splicing trans-factors for ESE are serine/arginine-rich (SR) proteins, which function as either an essential or regulatory factor. 3,4SR proteins can modulate several steps of spliceosome assembly through protein-protein and protein-RNA interaction.5,6 They possess one or two RNA-recognition motif (RRM) at the N-terminal end and arginine and serine residues (RS domains) at the C-terminal end. The majority of splicing trans-factors for splicing silencer elements (ISSs/ ESSs) are heterogeneous nuclear ribonucleoproteins (hnRNPs). 7Members of this family usually contain an RRM-type and KHtype RNA-bind...

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Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease

Cited by 71 publications

References 42 publications

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells

Decoding Abnormal Splicing Code in Human Diseases

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