Histone methyltransferase DOT1L controls state‐specific identity during B cell differentiation

Aslam, Muhammad; Alemdehy, Mir Farshid; Kwesi-Maliepaard, Eliza Mari; Muhaimin, Fitriari Izzatunnisa; Caganova, Marieta; Pardieck, Iris N.; Brand, Teun van den; Welsem, Tibor van; Rink, Iris de; Song, Ji‐Ying; Wit, Elzo de; Arens, Ramon; Jacobs, Heinz; Leeuwen, Fred van

doi:10.15252/embr.202051184

Cited by 34 publications

(58 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings indicate that AF10 acts as a safeguarding mechanism for somatic cell identity by enabling higher order H3K79 methylation of somatic-specific genes. Presence of higher order H3K79 methylation may antagonize gene repression, thereby preventing silencing of somatic transcriptional programs upon OSKM expression [ 15 , 32 ]. Alternatively, recent work points to a role for DOT1L in transcription initiation, and it will be interesting to investigate if AF10 plays a role in that process [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Uğurlu-Çimen

Odluyurt

Sevinç

et al. 2021

Epigenetics & Chromatin

View full text Add to dashboard Cite

Background The histone H3 lysine 79 (H3K79) methyltransferase DOT1L is a key chromatin-based barrier to somatic cell reprogramming. However, the mechanisms by which DOT1L safeguards cell identity and somatic-specific transcriptional programs remain unknown. Results We employed a proteomic approach using proximity-based labeling to identify DOT1L-interacting proteins and investigated their effects on reprogramming. Among DOT1L interactors, suppression of AF10 (MLLT10) via RNA interference or CRISPR/Cas9, significantly increases reprogramming efficiency. In somatic cells and induced pluripotent stem cells (iPSCs) higher order H3K79 methylation is dependent on AF10 expression. In AF10 knock-out cells, re-expression wild-type AF10, but not a DOT1L binding-impaired mutant, rescues overall H3K79 methylation and reduces reprogramming efficiency. Transcriptomic analyses during reprogramming show that AF10 suppression results in downregulation of fibroblast-specific genes and accelerates the activation of pluripotency-associated genes. Conclusions Our findings establish AF10 as a novel barrier to reprogramming by regulating H3K79 methylation and thereby sheds light on the mechanism by which cell identity is maintained in somatic cells.

show abstract

Section: Discussionmentioning

confidence: 99%

AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Uğurlu-Çimen

Odluyurt

Sevinç

et al. 2021

Epigenetics & Chromatin

View full text Add to dashboard Cite

show abstract

“…DOT1L-mediated selective histone 3 lysine 79 (H3K79me2/3) modifications at the IL-6 and IFN-b1 promoters are required for the full activation of innate immune responses (28). DO1L plays an important role in regulating the differentiation and complete function of CD4+, CD8+T cells and B cells in the process of acquired immunity, while DO1L knockdown or mutation invalidates acquired immunity (29)(30)(31)(32). ZBTB1 (zinc finger and BTB domain containing 1) prevents DNA damage in replicating immune progenitors, allowing the generation of B cells, T cells, and myeloid cells (33).…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

et al. 2021

View full text Add to dashboard Cite

PurposeTo construct a prognostic signature composed of DNA repair genes to effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC).MethodsAfter downloading the transcriptome and clinical data of HNSCC from the Cancer Genome Atlas (TCGA), 499 patients with HNSCC were equally divided into training and testing sets. In the training set, 13 DNA repair genes were screened using univariate proportional hazard (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a risk model, which was validated in the testing set.ResultsIn the training and testing sets, there were significant differences in the clinical outcomes of patients in the high- and low-risk groups showed by Kaplan-Meier survival curves (P < 0.001). Univariate and multivariate Cox regression analyses showed that the risk score had independent prognostic predictive ability (P < 0.001). At the same time, the immune cell infiltration, immune score, immune-related gene expression, and tumor mutation burden (TMB) of patients with HNSCC were also different between the high- and low-risk groups (P < 0.05). Finally, we screened several chemotherapeutics for HNSCC, which showed significant differences in drug sensitivity between the high- and low-risk groups (P < 0.05).ConclusionThis study constructed a 13-DNA-repair-gene signature for the prognosis of HNSCC, which could accurately and independently predict the clinical outcome of the patient. We then revealed the immune landscape, TMB, and sensitivity to chemotherapy drugs in different risk groups, which might be used to guide clinical treatment decisions.

show abstract

“…While Dot1L has very recently been shown to have a role in B cell differentiation and in CSR, and it is highly expressed in germinal center B cells (27), its role and that of H3K79me in V region mutation has not been examined in detail. To study this, we used the human Ramos Burkitt's lymphoma germinal centerlike B cell line that expresses AID and undergoes V region mutations (28).…”

Section: Significancementioning

confidence: 99%

Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes

Duan

Baughn

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Somatic hypermutation (SHM) and class-switch recombination (CSR) of the immunoglobulin (Ig) genes allow B cells to make antibodies that protect us against a wide variety of pathogens. SHM is mediated by activation-induced deaminase (AID), occurs at a million times higher frequency than other mutations in the mammalian genome, and is largely restricted to the variable (V) and switch (S) regions of Ig genes. Using the Ramos human Burkitt’s lymphoma cell line, we find that H3K79me2/3 and its methyltransferase Dot1L are more abundant on the V region than on the constant (C) region, which does not undergo mutation. In primary naïve mouse B cells examined ex vivo, the H3K79me2/3 modification appears constitutively in the donor Sμ and is inducible in the recipient Sγ1 upon CSR stimulation. Knockout and inhibition of Dot1L in Ramos cells significantly reduces V region mutation and the abundance of H3K79me2/3 on the V region and is associated with a decrease of polymerase II (Pol II) and its S2 phosphorylated form at the IgH locus. Knockout of Dot1L also decreases the abundance of BRD4 and CDK9 (a subunit of the P-TEFb complex) on the V region, and this is accompanied by decreased nascent transcripts throughout the IgH gene. Treatment with JQ1 (inhibitor of BRD4) or DRB (inhibitor of CDK9) decreases SHM and the abundance of Pol II S2P at the IgH locus. Since all these factors play a role in transcription elongation, our studies reinforce the idea that the chromatin context and dynamics of transcription are critical for SHM.

show abstract

Histone methyltransferase DOT1L controls state‐specific identity during B cell differentiation

Cited by 34 publications

References 91 publications

AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes

Contact Info

Product

Resources

About