T-Cell Super-Enhancers and Autoimmunity

[nandixon]

Has this already been posted somewhere?:

NIH researchers reveal link between powerful gene regulatory elements and autoimmune diseases

Bethesda, Md., Tues., Feb. 17, 2015 - Investigators with the National Institutes of Health (NIH) have discovered the genomic switches of a blood cell are key to regulating the human immune system. The findings, published in Nature today [reference], open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.

Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.

Dr. O'Shea's team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of Dr. Collins and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction.

Dr. O'Shea's team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease.

Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

But the researchers' most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs...

(More info in the links.)

 

[Jonathan Edwards]

Has this already been posted somewhere?:

NIH researchers reveal link between powerful gene regulatory elements and autoimmune diseases


(More info in the links.)

I find this a bit baffling. There is no evidence for anything wrong with T cells in RA, despite lots of immunologists being obsessed with this idea. Moreover, the genetic risks for RA do not lie in superenhancers - the main ones are the X chromosome (being female) and MHC Class II, expressed on B cells and other antigen presenting cells. This sound to me like somebody has found some bits of DNA and wants to make it sound as if they are important to a disease so that they can get grant funding!!

 

[nandixon]

Here is the abstract from PubMed (with a link to the same abstract in the original journal). I've broken it up for easier reading:

Nature. 2015 Feb 16. doi: 10.1038/nature14154. [Epub ahead of print]

Super-enhancers delineate disease-associated regulatory nodes in T cells.

Vahedi G1, Kanno Y1, Furumoto Y2, Jiang K1, Parker SC3, Erdos MR3, Davis SR4, Roychoudhuri R4, Restifo NP4, Gadina M2, Tang Z5, Ruan Y5, Collins FS3, Sartorelli V6, O'Shea JJ1.

Author information

Abstract

Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity.

Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease.

CD4+ T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification.

We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells.

Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2.

Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages.

Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures.

Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE.

Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.