Molecular mechanism of familial partial lipodystrophy
Familial partial lipodystrophy of Dunnigan type (FPLD2) belongs to a group of rare diseases called laminopathies. Laminopathies are caused by mutations in the LMNA gene encoding nuclear lamin A and its splice variant lamin C3. FPLD2 is characterised by lower-body lipoatrophy and upper body fat accumulation, severe insulin resistance, dyslipidaemia and early presentation of type 2 diabetes as well as early cardiovascular events. Thus FPLD2, although rare, recapitulates main features of obesity-related type 2 diabetes, but in a much more severe form. We propose that FPLD2 serves as a model system to study depot-specific adipose tissue dysfunctions and the common metabolic complications of common obesity-related adult chronic disease.
Lamins form a filamentous meshwork in the nuclear envelope and interacts with chromatin through lamina-associated domains as well as promoters and enhancers in the nuclear interior. The hotspot LMNA R482W mutation leading to FPLD impairs the interaction with DNA. We have pilot data to suggest that the long non-coding RNA HOTAIR interacts with LMNA. HOTAIR is specifically expressed in lower-body adipose tissue and targets the PRC2 complex. Indeed, several deregulated genes in models of FPLD2 are HOTAIR-dependent PRC2 targets and also involved in adipogenesis. This raises the possibility that R482W LMNA mutation impairs HOTAIR-dependent PRC2 recruitment, altering adipogenesis in a depot-specific manner. HOTAIR’s exclusive lower body expression displays a between-people highly expression that appears to be driven by DNA methylation so the epigenetic regulation of HOTAIR expression will be investigated with the aim of searching for mechanisms explaining the phenotypic diversity of FPLD2. The laboratory has the unique access to a large number of FPLD2 patients and to normal reference human tissues through the Oxford Biobank (www.oxfordbiobank.org.uk).
This DPhil project will capitalize on these preliminary findings to delineate this interaction and provide a mechanistic understanding of disease (FPLD) at molecular level.
The studies will involve the use of recently developed human regional-specific immortalized adipocytes, techniques to knock down and upregulate gene transcription as well as gene editing (CRISPR). Cellular phenotyping during differentiation processes using a range of different techniques. Transcriptional enhancer regions will be identified using ChipSeq. Parts of the project will be conducted in collaboration with Prof Philippe Collas, University of Oslo, Norway.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
|1||Todorčević M, Hilton C, McNeil C, Christodoulides C, Hodson L, Karpe F, Pinnick KE. A cellular model for the investigation of depot specific human adipocyte biology. Adipocyte. 2017;6:40-55.|
|2||Karpe F, Pinnick KE. Biology of upper-body and lower-body adipose tissue--link to whole-body phenotypes. Nat Rev Endocrinol. 2015;11:90-100|
|3||Pinnick KE, Nicholson G, Manolopoulos KN, McQuaid SE, Valet P, Frayn KN, Denton N, Min JL, Zondervan KT, Fleckner J; MolPAGE Consortium, McCarthy MI, Holmes CC, Karpe F. Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications. Diabetes. 2014;63:3785-97|