investigating regulation of splicing using next generation sequencing

平成26年3月23日 March 23, 2015
Tokuron Special Lecture
Pre-mRNA splicing in disease – investigating
regulation of splicing using next generation
Thomas Koed Doktor, Ph.D.
Department of Biochemistry and Molecular Biology,
University of Southern Denmark, Odense, Denmark
きた新進気鋭の若手研究者です。NGS in silico解析の最先端の講義です。
Pre-mRNA splicing is a fundamental process that regulates the vast majority of human genes. This process is
regulated by sequence elements known as splicing-regulatory elements (SREs). These SREs can function as either
enhancers that promote splicing of exons, usually by binding to SR proteins, or as silencers that repress splicing of exons
and usually bind hnRNP proteins. The interplay between these positively and negatively acting elements determine the
inclusion of exons in the mature transcripts.
Because the binding of splicing regulatory proteins to the SREs is sequence-dependent, mutations within the
SREs can lead to loss of binding of the splicing regulatory protein, which can affect splicing and lead to a decrease in the
production of fully functional mRNA, and therefore a loss of protein function. Identifying the SREs, and understanding how
they cooperate in regulating splicing is therefore important if we want to understand how mutations can cause aberrant
splicing and disease. Identification of important SREs additionally enables us to correct aberrant splicing by using spliceshifting oligos (SSOs) to block the access of splice-regulatory proteins to specific SREs.
The advent of next generation sequencing (NGS) has greatly improved our ability to globally detect effects on
splicing, and we use these techniques to examine known splicing-related disorders and to examine the functions of
individual splicing regulatory proteins.
One such splicing disorder is the neuromuscular disorder Spinal Muscular Atrophy (SMA), which is characterized
by loss of motor neurons. The SMN protein, which is decreased in SMA patients, is involved in assembly of key splicing
complexes and in my talk I will present data on our study on how decreased levels of SMN protein can affect splicing in a
mouse model of SMA.
Additionally, I will present some of our work on identifying hnRNP A1 binding sites as well as recent work on SSO
mediated correction of aberrant splicing in the MTRR gene.
2015 年 3 月 23 日(月) 午後 5 時から午後 6 時半
March 23, 2015 (Mon), 17:00 – 18:30
Meeting Room 2, 1st Floor of the Medical Research Building (next to COOP)
神経遺伝情報学 大野欽司 (秘書内線 2447)
Kinji Ohno, Neurogenetics (ext. 2447 for secretary)
No registration is required. A Tokuron lecture credit can be requested.