The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Gialitakis, Manolis; Sellars, MacLean; Littman, Dan R.

doi:10.1007/82_2011_175

Cited by 12 publications

(13 citation statements)

References 124 publications

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“…1H). To evaluate this possibility, we generated Cd4 -Cre Thpok fl/fl Cd4Sil fl/+ mice, in which Cre excises floxed alleles of Thpok and of the Cd4 silencer ( Cd4Sil ), a cis-regulatory element mediating Cd4 silencing in differentiating CD8 + -lineage thymocytes (39, 40). Even though silencer inactivation maintained CD4 expression, it failed to rescue Treg cell populations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Carpenter

Wohlfert

Chopp

et al. 2017

The Journal of Immunology

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The CD4+-lineage specific transcription factor Thpok is required for intrathymic CD4+ T cell differentiation and, together with its homolog LRF, supports CD4+ T cell helper effector responses. However, it is not known if these factors are needed for the T regulatory (Treg) arm of MHC-II responses. Here, by inactivating in mice the genes encoding both factors in differentiated Tregs, we show that Thpok and LRF are redundantly required to maintain the size and functions of the post-thymic Treg pool. They support IL 2-mediated gene expression and the functions of the Treg-specific factor Foxp3. Accordingly, Treg-specific disruption of Thpok and Lrf causes a lethal inflammatory syndrome similar to that resulting from Treg deficiency. Unlike in conventional T cells, Thpok and LRF functions in Tregs are not mediated by their repression of the transcription factor Runx3. Additionally, we found Thpok needed for the differentiation of thymic Treg precursors, an observation in line with the fact that Foxp3+ Tregs are CD4+ cells. Thus, a common Thpok-LRF node supports both helper and regulatory arms of MHC-II responses.

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Section: Resultsmentioning

confidence: 99%

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Carpenter

Wohlfert

Chopp

et al. 2017

The Journal of Immunology

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“…These results suggested that chromatin modification at the CD4 locus may correlate with CD4 transcription. To further test this, we analyzed the CD4 gene promoter (P), 5′enhancer (two separate amplicons, E1 and E2), and silencer (S) for chromatin marks associated with active and repressed transcription (33). We performed multiple independent chromatin immunoprecipitations (ChIP) followed by quantitative PCR for E, P, and S regulatory elements as well as for exons 2 and 10 (ex.2, ex.10).…”

Section: Resultsmentioning

confidence: 99%

“…Most remarkably, the 32080 line has cell-to cell variation in CD4 expression that resembles epigenetic variegation (36). The CD4 gene is known to be epigenetically regulated during normal T-cell ontogeny and the 32080 line provides a remarkable model for the developmental switch between two T-cell progenitor stages, the intermediate CD8 single positive (ISP) stage and the double positive (DP) stage (33). Unlike normal development, however, the 32080 CD4 - and CD4 + populations interconvert (Figure 7D).…”

Section: Discussionmentioning

confidence: 99%

LMO2 induces T-cell leukemia with epigenetic deregulation of CD4

Cleveland

Goodings

Tripathi

et al. 2014

Experimental Hematology

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In this study, we present a remarkable clonal cell line, 32080, derived from a CD2-Lmo2 transgenic T-cell leukemia with differentiation arrest at the transition from the intermediate single positive (ISP) to double positive (DP) stages of T-cell development. 32080 cells had a striking variegated pattern in CD4 expression. There was cell-to-cell variability with some cells expressing no CD4 and others expressing high CD4. The two populations were isogenic and yet differed in their rates of apoptosis and sensitivity to glucocorticoid. We sorted the 32080 line for CD4 positive or negative cells and observed them in culture. After one week, both sorted populations showed variegated CD4 expression like the parental line, showing that the two populations could interconvert. We determined that cell replication was necessary to transit from CD4+ to CD4- and CD4- to CD4+. Lmo2 knockdown decreased CD4 expression, while inhibition of intracellular Notch1 or HDAC activity, induced CD4 expression. Enforced expression of Runx1 repressed CD4 expression. We analyzed the CD4 locus by H3 chromatin immunoprecipitation and found silencing marks in the CD4- cells, and activating marks in the CD4+ population. The 32080 cell line is a striking model of ISP to DP T-cell plasticity and invokes a novel mechanism for Lmo2's oncogenic functions.

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“…In the immune system, the best-characterized example of epigenetic regulation concerns the silencing of the Cd4 gene in CD8+ thymocytes. A dedicated silencer region in the Cd4 locus is known to play a central role in the initiation of Cd4 silencing during CD8+ T cell development [14]. However, in mature CD8+ T cells, the silent state of the Cd4 locus and the chromatin properties that characterize the silent state can be stably maintained in the absence of the silencer [14, 15].…”

Section: The Challenges Of Embracing Complexitymentioning

confidence: 99%

“…A dedicated silencer region in the Cd4 locus is known to play a central role in the initiation of Cd4 silencing during CD8+ T cell development [14]. However, in mature CD8+ T cells, the silent state of the Cd4 locus and the chromatin properties that characterize the silent state can be stably maintained in the absence of the silencer [14, 15]. This finding suggests that the silencer helps establish a repressive chromatin structure that is stably maintained by a true epigenetic mechanism.…”

Section: The Challenges Of Embracing Complexitymentioning

confidence: 99%

Transcriptional regulation in the immune system: a status report

Smale

2014

Trends in Immunology

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Regulated changes in transcription play a central role in virtually all events that accompany the development of the immune system and its response to microbial and environmental cues. Over the past 30 years, a large number of proteins that regulate transcription in the immune system have been discovered and much has been learned about their mechanisms of action. However, the field remains in its infancy, with technical challenges and the complexity of gene regulation circuitry limiting our current knowledge and providing formidable barriers to further advancement. Despite these barriers, the development of new and increasingly sophisticated technologies is speeding progress toward an understanding of the gene-specific and global logic through which transcription is regulated in key immunological settings.

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The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Cited by 12 publications

References 124 publications

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

LMO2 induces T-cell leukemia with epigenetic deregulation of CD4

Transcriptional regulation in the immune system: a status report

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