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How to silence a stem cell gene expression program

Heatmaps showing the dynamic regulation of the epigenetic mark H3K27me3 during T cell differentiation (blue and yellow: low and high H3K27me3 levels), and the mRNA expression of the corresponding genes (green and red: low and high expression levels) in WT and Ikaros-deficient mice.

Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2.

Oravecz A(1), Apostolov A(1), Polak K(1), Jost B(2), Le Gras S(2), Chan S(1), Kastner P(1,)(3).

Nat Commun Nov. 9, 2015

Nov. 9, 2015

The differentiation of different types of blood cells is dependent on complex genetic and epigenetic programs. Attila Oravecz in the team of Susan Chan and Philippe Kastner uncovered a novel epigenetic regulatory mechanism in the early stages of the differentiation of T lympocytes controlled by the Ikaros transcription factor. Published on November 9th in Nature Communications, this study highlights the repressive role of the latter on many specific genes of hematopoietic stem cells. Ikaros recruits Polycomb complex PRC2 to deposit repressive epigenetic marks. This work highlights a new epigenetic repression mechanism that could explain the tumor suppressor function of Ikaros in leukemia.

Ikaros, guardian of T cell development
T cells are crucial effectors of the immune system. Derived from hematopoietic stem cells (the precursor cells of all blood cell lineages) located in the bone marrow, they develop in the thymus through a multi-step cell fate commitment and differentiation program. The T lineage commitment in particular requires the activation of a specific transcriptional program, but also the stable repression of stem cell-related programs. The inappropriate activation of stem cells properties in cells already committed to a differentiation pathway is also frequently involved in the appearance of cancer cells. The transcription factor Ikaros is a key regulator of gene expression during T cell development, acting as a tumor suppressor in both humans and mice.


Ikaros controls PRC2 in developing T cells
Attila Oravecz in Susan Chan and Philippe Kastner team investigated the role of Ikaros in the epigenetic control of T lymphocytes differentiation. By establishing epigenetic profiles at different stages of maturation of T cells, he showed that Ikaros was a mediator of the establishment and maintenance of the epigenetic mark H3K27me3 on more than 500 genomic regions. This epigenetic mark is controlled by the Polycomb repressive complex 2 (PCR2) and propagated through many cell generations, ensuring a stable repression of transcription in differentiated cells. The majority of the genes affected by the loss of Ikaros are normally selectively expressed in hematopoietic stem cells. In mice deficient for Ikaros, these genes remain expressed in T cell. Ikaros inactivation at different stages of T cell differentiation also showed that this factor is specifically required at an early stage of the maturation. These results show how a transcriptional factor can control the epigenetic extinction of a transcriptional program, and may be important to explain the persistent expression of stem cell genes in leukemias where the Ikaros gene is deleted.

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