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Institut de Génétique Moléculaire de Montpellier (IGMM) - UMR5535


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Home page > Research Groups > Eric SOLER - Molecular Hematopoiesis

Eric SOLER - Molecular Hematopoiesis

The major goal of the laboratory is to understand how genes are controlled in time and space during dynamic processes such as cellular differentiation and development. We use hematopoiesis, and specifically eythropoiesis, as a biological system to dissect the molecular events leading to fine tuning of gene expression, with strong emphasis on long-range genomic interactions, and associated pathological disorders in erythroid cells.

Our projects aim at unraveling the relationships existing between chromosome folding, genome architecture and gene expression during cellular differentiation and development. We use combination of functional genomics and proteomic tools to dissect the role of transcription factor complexes and chromatin regulatory factors in the establishment of chromatin looping, which is critical to create dynamic contacts between distal enhancers and target genes in vivo. We focus our attention on the LDB1 transcription factor complex, a major regulator of erythroid differentiation, allowing control of gene expression over long genomic distances (from several kb up to 1 Mb) through the establishment of chromatin loops. These types of long-range interactions are critical in gene regulatory networks and may be affected in several diseases. We showed for instance that long-range enhancer-gene interactions at the HBS1L-MYB locus are affected by genomic variants in beta-thalassemia patients, underscoring the need to decipher such long-range interactions across the genome and to understand their impacts on gene expression.

In this context we are focusing on different erythroid disorders such as beta thalassemias and sickle cell anemia, which are among the most common inherited genetic disorders in humans and acute erythroid leukemias, a rare but particularly aggressive subtype of leukemia for which therapeutic options are dramatically limited.

Figure Legend : Model of MYB oncogene regulation in erythroid cells. Sets of distal enhancer elements bound by the LDB1 transcription factor complex (orange ovals, numbers indicate distance in kb from MYB promoter) interact with the MYB gene promoter and first intron through chromatin loops. Transcription factor-bound regulatory elements cluster around MYB to form an active chromatin hub (ACH), stimulating transcription (left).Under normal conditions, terminal erythroid differentiation is accompanied by strong decrease in LDB1 complex binding at distal enhancer sites, loss of looping and dramatic decrease in MYB expression (top right). Presence of intergenic non-coding variants (Single Nucleotide Polymorphisms, or SNPs) affect local transcription factor binding at distal enhancer sites (here at -84kb enhancer) and diminish looping frequency and MYB expression (bottom righ), explaining the effect of trait-associated intergenic SNPs on MYB regulation. Lower MYB levels subsequently affect red cell traits.

Selected Recent publications :

Unbiased Interrogation of 3D Genome Topology Using Chromosome Conformation Capture Coupled to High-Throughput Sequencing (4C-Seq). Brouwer RW, van den Hout MC, van IJcken WF, Soler E, Stadhouders R. Methods Mol Biol. 2017;1507:199-220.

Enhancers and their dynamics during hematopoietic differentiation and emerging strategies for therapeutic action. Cico A, Andrieu-Soler C, Soler E. FEBS Lett. 2016 Oct 6. doi: 10.1002/1873-3468.12424. Review.

Control of developmentally primed erythroid genes by combinatorial co-repressor actions. Stadhouders R, Cico A, Stephen T, Thongjuea S, Kolovos P, Baymaz HI, Yu X, Demmers J, Bezstarosti K, Maas A, Barroca V, Kockx C, Ozgur Z, van Ijcken W, Arcangeli ML, Andrieu-Soler C, Lenhard B, Grosveld F, Soler E. Nat Commun. 2015 Nov 23;6:8893. doi: 10.1038/ncomms9893.

Long-range gene regulation and novel therapeutic applications. van den Heuvel A, Stadhouders R, Andrieu-Soler C, Grosveld F, Soler E. Blood. 2015 Mar 5;125(10):1521-5. doi: 10.1182/blood-2014-11-567925. Review.

HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W, Lenhard B, Rooks H, Best S, Menzel S, Grosveld F, Thein SL, Soler E. J Clin Invest. 2014 Apr;124(4):1699-710. doi: 10.1172/JCI71520.

Multiplexed chromosome conformation capture sequencing for rapid genome-scale high-resolution detection of long-range chromatin interactions. Stadhouders R, Kolovos P, Brouwer R, Zuin J, van den Heuvel A, Kockx C, Palstra RJ, Wendt KS, Grosveld F, van Ijcken W, Soler E. Nat Protoc. 2013 Mar;8(3):509-24. doi: 10.1038/nprot.2013.018.

Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development. Stadhouders R, Thongjuea S, Andrieu-Soler C, Palstra RJ, Bryne JC, van den Heuvel A, Stevens M, de Boer E, Kockx C, van der Sloot A, van den Hout M, van Ijcken W, Eick D, Lenhard B, Grosveld F, Soler E. EMBO J. 2012 Feb 15;31(4):986-99. doi: 10.1038/emboj.2011.450.


Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
FRANCE
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