共查询到20条相似文献,搜索用时 15 毫秒
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Roscoe Klinck Angélique Fourrier Philippe Thibault Johanne Toutant Mathieu Durand Elvy Lapointe Marie-Laure Caillet-Boudin Nicolas Sergeant Geneviève Gourdon Giovanni Meola Denis Furling Jack Puymirat Benoit Chabot 《PloS one》2014,9(9)
With the goal of identifying splicing alterations in myotonic dystrophy 1 (DM1) tissues that may yield insights into targets or mechanisms, we have surveyed mis-splicing events in three systems using a RT-PCR screening and validation platform. First, a transgenic mouse model expressing CUG-repeats identified splicing alterations shared with other mouse models of DM1. Second, using cell cultures from human embryonic muscle, we noted that DM1-associated splicing alterations were significantly enriched in cytoskeleton (e.g. SORBS1, TACC2, TTN, ACTN1 and DMD) and channel (e.g. KCND3 and TRPM4) genes. Third, of the splicing alterations occurring in adult DM1 tissues, one produced a dominant negative variant of the splicing regulator RBFOX1. Notably, half of the splicing events controlled by MBNL1 were co-regulated by RBFOX1, and several events in this category were mis-spliced in DM1 tissues. Our results suggest that reduced RBFOX1 activity in DM1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1. 相似文献
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细胞凋亡(apoptosis)是多细胞生物的一种基本生命活动,在机体的生长发育、免疫调节及维持内环境稳定等各方面扮演着重要的角色.遗传和生化研究表明,细胞凋亡受到复杂而精细的调控.转录水平、翻译后水平等各种层次的调控,构成了一个复杂的凋亡调控网络. 相似文献
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Pre-mRNA选择性剪接是真核生物转录组和蛋白质组多样性的主要来源,也是细胞分化、发育等过程中重要的基因表达调控方式。约95%的人类多外显子基因存在RNA选择性剪接|很多人类基因疾病的发生与RNA剪接错误相关。随着共转录现象的发现,RNA选择性剪接调控机制研究也取得了很大进展。本文分别从序列层面和核小体定位、组蛋白修饰、DNA甲基化及非编码RNA等表观遗传层面,系统地阐述了RNA选择性剪接的调控机制。为便于搜索,本文介绍了近10年来RNA选择性剪接相关的数据库。 相似文献
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Mandy S. Wong Ling Chen Christopher Foster Radhika Kainthla Jerry W. Shay Woodring E. Wright 《Cell reports》2013,3(4):1028-1035
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大多数真核基因能够发生可变剪接,其调控对于生理和病理状态下细胞功能的实现至关重要,而异常可变剪接则可导致多种疾病。虽然已知可变剪接能够在转录后水平调节基因表达,然而目前仍不清楚特定的可变剪接模式是如何被调控的。越来越多的研究发现细胞信号和外界环境刺激能够调控靶基因的剪接模式,并且已发现一些与可变剪接调控有关的信号转导通路,而后者能够通过修饰剪接因子进而改变剪接因子的亚细胞定位或者活性,从而实现对靶基因可变剪接模式的调控。由细胞信号转导通路所构成的网络能够灵活多样地调控基因剪接,一条信号通路可调控多个基因剪接,而多条信号通路也可调控同一基因剪接,对于理解信号转导过程的分子机制具有重要意义。 相似文献
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Joseph T. Roland Lynne A. Lapierre James R. Goldenring 《The Journal of biological chemistry》2009,284(2):1213-1223
Rab proteins influence vesicle trafficking pathways through the assembly of
regulatory protein complexes. Previous investigations have documented that
Rab11a and Rab8a can interact with the tail region of myosin Vb and regulate
distinct trafficking pathways. We have now determined that a related Rab
protein, Rab10, can interact with myosin Va, myosin Vb, and myosin Vc. Rab10
localized to a system of tubules and vesicles that have partially overlapping
localization with Rab8a. Both Rab8a and Rab10 were mislocalized by the
expression of dominant-negative myosin V tails. Interaction with Rab10 was
dependent on the presence of the alternatively spliced exon D in myosin Va and
myosin Vb and the homologous region in myosin Vc. Yeast two-hybrid assays and
fluorescence resonance energy transfer studies confirmed that Rab10 binding to
myosin V tails in vivo required the alternatively spliced exon D. In
contrast to our previous work, we found that Rab11a can interact with both
myosin Va and myosin Vb tails independent of their splice isoform. These
results indicate that Rab GTPases regulate diverse endocytic trafficking
pathways through recruitment of multiple myosin V isoforms.Eukaryotic cells are comprised of networks of highly organized membranous
structures that require the efficient and timely movement of diverse
intracellular proteins for proper function. Molecular motors provide the
physical force needed to move these materials along microtubules and actin
microfilaments. Unconventional myosin motors, such as those belonging to
classes V, VI, and VII, have roles in the trafficking and recycling of
membrane-bound structures in eukaryotic cells
(1) and are recruited to
discrete vesicle populations. Myosin VI is involved in clathrin-mediated
endocytosis (2), whereas myosin
VIIa participates in the proper development of stereocilia of inner ear hair
cells and the transport of pigment granules in retinal pigmented epithelial
cells (3,
4). Similarly, the three
members of vertebrate class V myosins, myosin Va, myosin Vb, and myosin Vc,
are required for the proper transport of a wide array of membrane cargoes,
such as the melanosomes of pigment cells, synaptic vesicles in neurons, apical
recycling endosomes in polarized epithelial cells, and bulk recycling vesicles
in non-polarized cells (5).Members of the Rab family of small GTPases regulate many cellular systems,
including membrane trafficking
(6,
7). Certain Rab proteins
associate with and regulate the function of class V myosins. Rab27a, in a
complex with the adaptor protein melanophilin/Slac2-a, is required to localize
myosin Va to the surface of melanin-filled pigment granules in vertebrates
(8-10),
whereas Rab27a and Slac2-c/MyRIP associate with both Myosin Va and myosin VIIa
(3,
11). Rab11a, in a complex with
its adaptor protein Rab11-FIP2, associates with myosin Vb on recycling
endosomes
(12-14)
where the tripartite complex regulates the recycling of a variety of cargoes
(15-19).
In addition, Rab8a associates with both myosin Vb
(20) and myosin Vc
(21) as part of the
non-clathrin-mediated tubular recycling system
(20). Recently, Rab11a has
also been shown to associate with myosin Va in the transport of AMPA receptors
in dendritic spines (22),
contributing to the model of myosin V regulation by multiple Rab proteins.Previous investigations have documented alternative splicing of myosin Va
in a tissue-specific manner
(23-28).
Alternate splicing occurs in a region lying between the coiled-coil region of
the neck of the motor and the globular tail region. Three exons in particular
are subject to alternative splicing: exons B, D, and F
(23-25).
Exon F is critical for association with melanophilin/Slac2 and Rab27a
(8,
9,
29,
30). Additionally, exon B is
required for the interaction of myosin Va with dynein light chain 2 (DLC2)
(27,
28). Currently no function for
the alternatively spliced exon D has been reported. Similar to myosin Va,
myosin Vb contains exons A, B, C, D, and E, whereas no exon F has yet been
identified in myosin Vb (Fig.
1A). In addition, exon B in myosin Vb does not resemble
the dynein light chain 2 (DLC2) binding region in myosin Va
(27,
28), and therefore, it likely
does not interact with DLC2. On the other hand, exon D is highly conserved
among Myosin Va, myosin Vb, and myosin Vc, suggesting a common function in
these molecular motors.Open in a separate windowFIGURE 1.Tissue distribution of human myosin Va and myosin Vb splice
isoforms. A, schematic of the alternative exon organization in
the tails of myosin Va and myosin Vb. It is known that exons B, D, and F are
subject to alternative splicing in myosin Va, whereas there is only evidence
that exon D is alternatively spliced in myosin Vb, which does not contain exon
F. B, alignment of exon D sequences from mouse and human myosin V''s.
myosin Va and myosin Vb both contain exon D (amino acids 1320-1346 of myosin
Va and 1315-1340 of myosin Vb), whereas myosin Vc contains an exon D-like
region (amino acids 1124-1147 of human myosin Vc) that is not known to be
alternatively spliced. Alignment of the exon D regions from all three motors
reveals a high degree of homology, especially in the center of the exon.
Asterisks indicate amino acid identities. C, PCR-based
analysis of human tissue panels reveals the alternative splicing pattern of
exon D in myosin Va and myosin Vb. Primers flanking the region encoding exon D
for both motors were used to amplify cDNA from human MTC™ panels
(Clontech). cDNA amplified from HeLa cell RNA as well as myosin Va and myosin
Vb tail constructs were used as positive controls. Variants expressing exon D
(upper bands) and lacking exon D (lower bands) were visible.
Per., peripheral; Pos., positive.Here we report that Rab10, a protein related to Rab8a and thought to have
similar function
(31-35),
localizes to a system of tubules and vesicles overlapping in distribution with
Rab8a in HeLa cells. Utilizing dominant-negative myosin V tail constructs, we
show that Rab8a and Rab10 can interact with Myosin Va, myosin Vb, and myosin
Vc in vivo. In addition, we have determined that the alternatively
spliced exon D in both myosin Va and myosin Vb is required for interaction
with Rab10. In contrast to our previous findings, we demonstrate that Rab11a
is able to interact with both myosin Va and myosin Vb tails in an exon
independent-manner. These results reveal that multiple Rab proteins
potentially regulate all three class V myosin motors. 相似文献
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长链非编码RNA (lncRNA)选择性剪接是指剪除未成熟lncRNA中的内含子,并将外显子连接起来生成成熟lncRNA的过程.在各类疾病发生和发展过程中,异常的选择性剪接起着重要作用. lncRNA选择性剪接直接参与膀胱癌、结直肠癌、肝癌、神经母细胞瘤等多种肿瘤的发病机制,且与胚胎发育、软骨毛发发育、多系统萎缩症等紧密相关.在此,我们对lncRNA选择性剪接的起因、调控机制以及对疾病影响的研究进展进行综述.此外,本文还介绍了两个与lncRNA选择性剪接相关的数据库(SpliceMap和LNCediting). 相似文献
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Alternative splicing is tightly regulated in a spatio-temporal and quantitative manner. This regulation is achieved by a complex interplay between spliceosomal (trans) factors that bind to different sequence (cis) elements. cis-elements reside in both introns and exons and may either enhance or silence splicing. Differential combinations of cis-elements allows for a huge diversity of overall splicing signals, together comprising a complex ‘splicing code’. Many cis-elements have been identified, and their effects on exon inclusion levels demonstrated in reporter systems. However, the impact of interspecific differences in these elements on the evolution of alternative splicing levels has not yet been investigated at genomic level. Here we study the effect of interspecific differences in predicted exonic splicing regulators (ESRs) on exon inclusion levels in human and chimpanzee. For this purpose, we compiled and studied comprehensive datasets of predicted ESRs, identified by several computational and experimental approaches, as well as microarray data for changes in alternative splicing levels between human and chimpanzee. Surprisingly, we found no association between changes in predicted ESRs and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5′ splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little or no effect on splicing, and thus interspecific changes at short-time scales may primarily occur in these effectively neutral ESRs. These results underscore the difficulties of using current computational ESR prediction algorithms to identify truly functionally important motifs, and provide a cautionary tale for studies of the effect of SNPs on splicing in human disease. 相似文献
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交替剪接是转录后修饰的一个重要过程,它很好的解释了基因数量有限性和蛋白质多样性之间巨大差异的问题。交替剪接能够调控细胞的多种生物学行为,比如增殖、分化和发育等,而且与许多疾病的发生相关,包括癌症。干细胞多能性维持和分化的研究大多集中在转录因子、染色质重塑和非编码RNA上,交替剪接概念的引入为干细胞研究提供了一个新的视角。该文综述了干细胞交替剪接调控的最新研究,首先简述了不同类型的干细胞(全能干细胞、多能干细胞和专能干细胞)中存在的交替剪接事件;其次,从四个方面阐述了交替剪接对干细胞多能性的调控;最后,系统地总结了干细胞向神经组织、肌肉组织、造血系统、脂肪组织和骨组织分化过程中发生的交替剪接事件。这些研究充分说明了未来干细胞领域的研究中,交替剪接是不可或缺的一部分。 相似文献
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2-羟基植烷酸辅酶A裂解酶(2-hydroxypanthyl-CoA lyase,HPCL2)是3-甲基脂肪酸α-氧化途径中的关键酶.采用鸟枪法测序技术,得到了HPCL2基因的基因组序列.结果显示,HPCL2基因组大小为40 829 bp,共有17个外显子,16个内含子.外显子平均大小为116 bp,内含子平均大小为2 429 bp,属于结构紧凑基因.从dbEST数据库中筛选与HPCL2基因的mRNA (GenBank Acc.:AJ131753) 相互重叠表达序列标签(EST)共有213个,分别来自29个不同的组织.将EST与基因组序列进行Blast分析,共检测17个EST具有选择性剪切,其中14例属外显子遗漏(exon skipping),2例外显子增加 (exon inclusion)和1例剪切位点改变(splicing site shift).外显子遗漏主要发生在5′端的第3到第8个外显子.结果表明,外显子遗漏可能是HPCL2基因选择性剪切的主要形式. 相似文献