The number of obesity cases has doubled since 1980: in 2014, over 600 million adults were affected across the world. The causes of this epidemic include unbalanced diet, as well as environmental and genetic factors. French INRA researchers, in association with colleagues from the Institut Pasteur, Inserm, CNRS and the University of Cambridge (UK), reveal that an epigenetic factor, the BAHD1 protein, participates in the regulatory mechanisms of cholesterol levels and weight gain. These results published on March 3rd 2016 in the journal PLoS Genetics could open new ways for finding therapies against obesity, diabetes and cardiovascular diseases.
Deficiency in BAHD1 leads to hypocholesterolemia and lower body fat.
In humans and other vertebrates BAHD1 is a protein making certain genes less active or even completely inactive, by compacting certain regions of chromosomes. So far, the physiological role of BAHD1 was unknown. To better characterize this protein, researchers have produced mice that do not have the BAHD1 gene. At birth, these mice are small. During growth, they recover the size of mice in which BAHD1 is expressed, but display lower levels of cholesterol and glucose in the blood and a lower body fat mass than control mice. Ablation of BAHD1 also causes a malfunction of the placenta and a reduction of the fetal weight. BAHD1 is therefore a key element in the control of placental development during the embryonic life and of the storage of body fat during the adult life.
Scientists have also searched for genes deregulated by BAHD1 deficiency in mice, or in vitro by BAHD1 overexpression in human cells. They found that in these two models, BAHD1 alters the expression of several genes involved in metabolic control of cholesterol, steroid hormones, lipids and sugars.
The BAHD1 protein, a key component of an epigenetic mechanism.
This study also demonstrates that BAHD1 acts with other proteins (such as enzymes called histone deacetylases and methyltransferases) to trigger so-called “epigenetic changes”. These epigenetic variations modulate the activity of genes, not as a result of mutations in the DNA sequence but of changes in the state of DNA compaction due to chemical modifications of DNA and histone proteins (in which DNA is wound, forming a fiber called chromatin). For example, BAHD1 regulates the expression of a gene encoding a receptor to estrogens (which are sexual hormones influencing weight) by acting on DNA and histone methylation in the region of this gene.
This work shows that epigenetic mechanisms act in the storage or consumption of energy in the body, at different stages of life. Targeted approaches in certain tissues on BAHD1, its partners or its target genes, may open new ways to find therapies against obesity, diabetes and cardiovascular diseases.
Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism, PLoS Genetics, March 3, 2016
Goran Lakisic, Alice Lebreton, Renaud Pourpre, Olivia Wendling, Emanuele Libertini, Elizabeth J. Radford, Morwenna Le Guillou, Marie-France Champy, Marie Wattenhofer-Donzé, Guillaume Soubigou, Slimane Ait-Si-Ali, Jean Feunteun, Tania Sorg, Jean-Yves Coppée, Anne C. Ferguson-Smith, Pascale Cossart, Hélène Bierne