The histone methyltransferase DOT1L is essential for humoral immune responses

Kealy, Liam; Pietro, Andrea Di; Scheer, Sebastian; Dalit, Lennard; Groom, Joanna R; Zaph, Colby; Good-Jacobson, Kim L

doi:10.1101/821462

Cited by 3 publications

(5 citation statements)

References 53 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B cell-specific ablation of Dot1l in mice hampers germinal center formation and humoral responses, with reduced IgM and switched antibodies 29,75 . Dot1l was shown to have a B cell-intrinsic role in CSR to IgG1 in purified mouse B cells stimulated ex vivo, albeit the effect depended on the stimulus and the mechanism was not explored 29 .…”

Section: Discussionmentioning

confidence: 99%

DOT1L limits RNAPII promoter-proximal pause release thus enabling Activation Induced Deaminase activity genome-wide

Subramani,

Seija,

Ridani

et al. 2023

Preprint

View full text Add to dashboard Cite

Activation induced deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation of the antibody genes but also mutates “off-target” genes, with oncogenic consequences. Understanding the mechanisms that render such loci susceptible to AID is therefore necessary. We identify the H3K79 histone methyltransferase DOT1L as a nuclear AID-proximal factor required for CSR and AID off-target activity, including IgH-cMyc translocations. Mechanistically, DOT1L limits promoter-proximal transcriptional pause release. DOT1L inactivation reduced promoter-proximal paused RNA polymerase II (RNAPII) occupancy, while concomitantly increasing RNAPII Serine 2 phosphorylation and reducing cohesin at gene bodies. These changes were proportional to the amount of H3K79me3 lost and perturbed transcription elongation, as evidenced by downregulation of highly expressed long genes but upregulation of shorter primed genes. Thus, DOT1L restricting promoter-proximal pause release can explain the hitherto puzzling predominance of gene upregulation in DOT1L-deficient mammalian cells and establishes regulated pause release as a critical step for AID activity.

show abstract

Section: Discussionmentioning

confidence: 99%

DOT1L limits RNAPII promoter-proximal pause release thus enabling Activation Induced Deaminase activity genome-wide

Subramani,

Seija,

Ridani

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Inhibition of HDACs in human CD4 + T cells induces regulatory T cell differentiation and affects cytokine expression (Ellmeier and Seiser, 2018). Given the important roles of HDAC and DOT1L in lymphocytes (Haery et al, 2015;Ellmeier and Seiser, 2018;Kealy et al, 2020;Kwesi-Maliepaard et al, 2020;Scheer et al, 2020;Aslam et al, 2021;Wille and Sridharan, 2022) it would certainly be interesting the assess the effect of HDAC inhibitors in combination with DOT1L inhibitors on normal immune cells and in other types of lymphoma. Taken together, although we could not find synergistic or suppressive effects of HDAC-and DOT1Linhibitors in CTCL during short term in vitro cell culture, the crosstalk between HDAC and DOT1L still warrants further investigation, especially in the context of in vivo immune responses.…”

Section: Discussionmentioning

confidence: 99%

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

et al. 2022

View full text Add to dashboard Cite

Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation.

show abstract

“…The findings of the studies by Scheer et al 5 . and Kealy et al 6 . provide a thorough insight into the functions of DOT1L in B and T cells and greatly expand our understanding of how gene expression in lymphocytes is regulated.…”

mentioning

confidence: 91%

“…Despite the emerging roles for DOT1L in various cell types and diseases, its function in the immune system was, until recently, largely uncharacterised. In two recent articles, studies by Sebastian Scheer and colleagues 5 and Liam Kealy and colleagues 6 define critical regulatory functions for DOT1L in T and B lymphocytes. Because DOT1L deficiency leads to embryonic lethality in mice, 7 both studies utilise conditional knockout (KO) mouse models to investigate DOT1L function in specific populations of T and B lymphocytes.…”

mentioning

confidence: 99%

“…Appearing back‐to‐back in the issue of Cell Reports is an independent study from Kealy et al . that find a central role for DOT1L in the differentiation and function of B lymphocytes 6 . The authors employ two different strategies for deletion of DOT1L and an extensive range of immunological challenges to convincingly define the involvement of DOT1L in the humoral immune response.…”

mentioning

confidence: 99%

See 1 more Smart Citation