Genomes are organized into high-level 3-dimensional structures, and DNA elements separated by long genomic distances could functionally interact. Many transcription factors bind to regulatory DNA elements distant from gene promoters. While distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Therefore, we developed Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) for de novo detection of global chromatin interactions, and comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ERα) in the human genome. We found that most high-confidence remote ERα binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ERα functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes.

Besides the estrogen receptor response elements (EREs), estrogen receptor-α binding is augmented by FOXA1 co-binding, the presence of the histone mark, histone 3 monomethylated at the lysine 4 position and the presence of open chromatin.The major determinant of ER binding is the strength of the ERE.The differences in estrogen receptor-binding profiles between breast cancer cell lines appear to be at sites with less ‘attractive' EREs but modulated by the non-sequence factors.

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.