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    Mechanisms of MAP Kinase Signaling to Transcriptional Regulators

    Teoh, Peik Lin

    [Thesis]. Manchester, UK: The University of Manchester; 2011.

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    Abstract

    The MAPK pathway is important in various biological functions. It is also important in regulating processes associated with gene transcription via different mechanisms such as by phosphorylation of transcription factors, coactivators/corepressors and histone modifier complexes. H3K4 methylation is highly associated with active transcription. Deposition of this mark is catalysed by SET-domain methyltransferases which consists of a WAR complex (WDR5, ASH2L and RBBP5), a catalytic SET-domain protein and other subunits. However, potential links between ERK MAPK signaling and H3K4 methylation in gene expression are not well understood. Thus, the aim of this study was to probe the potential links between these two pathways towards gene-regulatory networks. This study attempted to elucidate their direct functional interaction by studying whether components of the SETD1A complex could be phosphorylated upon ERK activation. Our results showed that the core components of SETD1A complex were not phosphorylated in vivo and in vitro by ERK. Importantly, we reported that at least two splicing variants of RBBP5 exist. ERK-dependent stabilization of exogenous RBBP5 was observed but the mechanism underlying this is unknown. Surprisingly, we found that WAR complex depletion increased the pre-mRNA expression of immediate-early (IE) genes which did not necessarily reflect changes in their mRNA levels. In addition, this occurred in an H3K4me3-independent manner. This regulation is likely to be posttranscriptional that involves pre-mRNA processing events. First, we noticed a decrease of transcription initiation in WAR complex-depleted cells upon ERK activation. Second, depletion of the WAR complex affects the splicing efficiency of FOS and EGR1. Third, RBBP5 occupancy was observed and was significantly reduced upon siRNA-mediated RBBP5 depletion at the coding region and the 3’ end of FOS gene. Therefore, we propose that the WAR complex regulates the pre-mRNA processing of IE genes through an interaction between RBBP5 and a splicing factor that has yet to be identified.

    Bibliographic metadata

    Type of resource:
    Content type:
    Administered thesis
    Form of thesis:
    Traditional
    Type of submission:
    Doctoral level ETD - final
    Thesis title:
    Mechanisms of MAP Kinase Signaling to Transcriptional Regulators
    Degree type:
    Doctor of Philosophy
    Degree programme:
    PhD Gene Expression
    Publication date:
    2011-12-14T13:06:47
    Institution:
    The University of Manchester
    Location:
    Manchester, UK
    Total pages:
    173
    Abstract:
    The MAPK pathway is important in various biological functions. It is also important in regulating processes associated with gene transcription via different mechanisms such as by phosphorylation of transcription factors, coactivators/corepressors and histone modifier complexes. H3K4 methylation is highly associated with active transcription. Deposition of this mark is catalysed by SET-domain methyltransferases which consists of a WAR complex (WDR5, ASH2L and RBBP5), a catalytic SET-domain protein and other subunits. However, potential links between ERK MAPK signaling and H3K4 methylation in gene expression are not well understood. Thus, the aim of this study was to probe the potential links between these two pathways towards gene-regulatory networks. This study attempted to elucidate their direct functional interaction by studying whether components of the SETD1A complex could be phosphorylated upon ERK activation. Our results showed that the core components of SETD1A complex were not phosphorylated in vivo and in vitro by ERK. Importantly, we reported that at least two splicing variants of RBBP5 exist. ERK-dependent stabilization of exogenous RBBP5 was observed but the mechanism underlying this is unknown. Surprisingly, we found that WAR complex depletion increased the pre-mRNA expression of immediate-early (IE) genes which did not necessarily reflect changes in their mRNA levels. In addition, this occurred in an H3K4me3-independent manner. This regulation is likely to be posttranscriptional that involves pre-mRNA processing events. First, we noticed a decrease of transcription initiation in WAR complex-depleted cells upon ERK activation. Second, depletion of the WAR complex affects the splicing efficiency of FOS and EGR1. Third, RBBP5 occupancy was observed and was significantly reduced upon siRNA-mediated RBBP5 depletion at the coding region and the 3’ end of FOS gene. Therefore, we propose that the WAR complex regulates the pre-mRNA processing of IE genes through an interaction between RBBP5 and a splicing factor that has yet to be identified.
    Keyword(s):
    Thesis main supervisor(s):
    Thesis co-supervisor(s):
    Thesis advisor(s):
    Funder(s):
    Degree grantor:
    Language:
    en

    Institutional metadata

    University researcher(s):
    Academic department(s):

    Record metadata

    Manchester eScholar ID:
    uk-ac-man-scw:140494
    Created by:
    Teoh, Peik Lin
    Created:
    14th December, 2011, 13:06:48
    Last modified by:
    Teoh, Peik Lin
    Last modified:
    2nd March, 2018, 10:30:12

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