Biology subjects

Wendy Bickmore

Publications and source records attributed to Wendy Bickmore.

2 recordsLinked to original sources

bioRxiv2016

Psip1/p52 regulates distal Hoxa genes through activation of lncRNA Hottip

Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including regulation of gene expression, X-inactivation, imprinting, cell proliferation and differentiation. However, the functionality of lncRNAs is not clearly understood and conflicting conclusions have often been reached when comparing different methods to investigate them. Moreover, little is known about the upstream regulation of lncRNAs. Here we show that a transcriptional co activator - PC4 and SF2 interacting protein (Psip1)/p52, which is involved in linking transcription to RNA processing, regulates the expression of the lncRNA Hottip. Using complementary approaches - knockdown, Cas9 mediated lncRNA deletion, analysis of lncRNA binding by Chromatin isolation by RNA purification (ChIRP) - we demonstrate that Hottip binds to the 5 Hoxa genes located in cis, which leads to their upregulation. Moreover, the synthetic activation of Hottip is sufficient to induce the expression ofpolycomb repressed Hox genes in mouse embryonic stem cells (mESCs).

Genetics↗

bioRxiv2016

Expression of progerin does not result in an increased mutation rate.

In the premature ageing disease Hutchinson-Gilford progeria syndrome (HGPS) the underlying genetic defect in the lamin A gene leads to accumulation at the nuclear lamina of progerin - a mutant form of lamin A that cannot be correctly processed. This has been reported to result in defects in the DNA damage response and in DNA repair, leading to the hypothesis that, as in normal ageing and in other progeroid syndromes caused by mutation of genes of the DNA repair and DNA damage response pathways, increased DNA damage may be responsible for the premature ageing phenotypes in HGPS patients. However, this hypothesis is based upon the study of markers of the DNA damage response, rather than measurement of DNA damage per se or the consequences of unrepaired DNA damage -mutation. Here, using a mutation reporter cell line, we directly compared the inherent and induced mutation rates in cells expressing wild-type lamin A or progerin. We find no evidence for an elevated mutation rate in progerin-expressing cells. We conclude that the cellular defect in HGPS cells does not lie in the repair of DNA damage per se.

Cell Biology↗