3D chromatin reprogramming primes human memory T H 2 cells for rapid recall and pathogenic dysfunction.
Anne Onrust-van SchoonhovenMarjolein J W de BruijnBernard S StikkerRutger W W BrouwerGerrit Johannes BraunstahlWilfred F J Van IJckenThomas GrafDanny HuylebroeckRudi W HendriksGrégoire StikRalph StadhoudersPublished in: Science immunology (2023)
Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4 + memory T helper 2 (T H 2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory T H 2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory T H 2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.
Keyphrases
- transcription factor
- gene expression
- working memory
- induced apoptosis
- genome wide
- genome wide identification
- oxidative stress
- dna binding
- cell cycle arrest
- dna damage
- endothelial cells
- blood pressure
- induced pluripotent stem cells
- cell death
- quality improvement
- minimally invasive
- signaling pathway
- hiv infected
- single cell
- long noncoding rna
- pi k akt
- binding protein
- heat shock
- antiretroviral therapy
- allergic rhinitis
- quantum dots