Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

Yang, Jing; McGovern, Amanda; Martin, Paul; Duffus, Kate; Ge, Xin; Zarrineh, Peyman; Morris, Andrew P.; Adamson, Antony; Fraser, Peter; Rattray, Magnus; Eyre, Stephen

doi:10.1038/s41467-020-18180-7

Cited by 50 publications

(53 citation statements)

References 52 publications

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“…In the past years, several studies started revisiting the 3D chromatin reorganization upon T cell activation using technologies that allow quantitation on a genome-wide scale. A recent study in human CD4 + reported that upon 24h of TCR activation, about 30% of long-range chromatin interactions undergo significant changes, while compartments or TADs remain unaffected (113). In agreement, another study combining ATAC-seq, in situ Hi-C and RNA-seq in human CD4 + and CD8 + cells before and after in vitro TCR stimulation for 72h, reported only minimal changes in compartmentalization.…”

Section: T Cellssupporting

confidence: 61%

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

2021

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Proper lymphopoiesis and immune responses depend on the spatiotemporal control of multiple processes, including gene expression, DNA recombination and cell fate decisions. High-order 3D chromatin organization is increasingly appreciated as an important regulator of these processes and dysregulation of genomic architecture has been linked to various immune disorders, including lymphoid malignancies. In this review, we present the general principles of the 3D chromatin topology and its dynamic reorganization during various steps of B and T lymphocyte development and activation. We also discuss functional interconnections between architectural, epigenetic and transcriptional changes and introduce major key players of genomic organization in B/T lymphocytes. Finally, we present how alterations in architectural factors and/or 3D genome organization are linked to dysregulation of the lymphopoietic transcriptional program and ultimately to hematological malignancies.

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Section: T Cellssupporting

confidence: 61%

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

2021

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“…Our CCA analysis shows that by aligning samples using shared structures we were able to identify known cell subtypes and characterise the transcriptome of these subtypes, as well as their response to stimulation. Again, while the effect of stimulation has been shown to be similar between samples in bulk RNA-seq 23 , increased sample numbers would be required to confirm this in scRNA-seq. Despite this, these findings suggest it is possible to directly compare samples with different disease activities, an essential step in studies investigating treatment response.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of CD4+ T-cell subtypes using single cell RNA sequencing and the impact of cell number and sequencing depth

Ding

Smith

Orozco

et al. 2020

Sci Rep

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CD4+ T-cells represent a heterogeneous collection of specialised sub-types and are a key cell type in the pathogenesis of many diseases due to their role in the adaptive immune system. By investigating CD4+ T-cells at the single cell level, using RNA sequencing (scRNA-seq), there is the potential to identify specific cell states driving disease or treatment response. However, the impact of sequencing depth and cell numbers, two important factors in scRNA-seq, has not been determined for a complex cell population such as CD4+ T-cells. We therefore generated a high depth, high cell number dataset to determine the effect of reduced sequencing depth and cell number on the ability to accurately identify CD4+ T-cell subtypes. Furthermore, we investigated T-cell signatures under resting and stimulated conditions to assess cluster specific effects of stimulation. We found that firstly, cell number has a much more profound effect than sequencing depth on the ability to classify cells; secondly, this effect is greater when cells are unstimulated and finally, resting and stimulated samples can be combined to leverage additional power whilst still allowing differences between samples to be observed. While based on one individual, these results could inform future scRNA-seq studies to ensure the most efficient experimental design.

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“…Nuclear translocation of NFκB binds to κB elements in target inflammatory response genes, turning them on 28 . Remodeling of these pathways at the chromatin level represents a key regulatory mechanism of the inflammatory response 29 . In addition to these inflammatory pathways, we identified chromatin remodeling at multiple pathways that mediated T-cell metabolic states and control of the cell cycle..…”

Section: Discussionmentioning

confidence: 99%

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation

Iqbal

Serralha

Kaur

et al. 2021

Sci Rep

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T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naïve T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of individual chromatin accessibility peaks that are associated with T-cell activation, the majority of which were annotated intronic and intergenic enhancer regions. A core set of 3268 gene promoters underwent chromatin remodeling and concomitant changes in gene expression in response to activation, and were enriched in multiple pathways controlling cell cycle regulation, metabolism, inflammatory response genes and cell survival. Leukemia inhibitory factor (LIF) was among those factors that gained the highest accessibility and expression, in addition to IL2-STAT5 dependent chromatin remodeling in the T-cell activation response. Using publicly available data we found the chromatin response was far more dynamic at 24-h compared with 72-h post-activation. In total 546 associations were reproduced at both time-points with similar strength of evidence and directionality of effect. At the pathways level, the IL2-STAT5, KRAS signalling and UV response pathways were replicable at both time-points, although differentially modulated from 24 to 72 h post-activation.

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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

Cited by 50 publications

References 52 publications

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

Characterisation of CD4+ T-cell subtypes using single cell RNA sequencing and the impact of cell number and sequencing depth

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation

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