Biology subjects

Kwesi-Maliepaard, E. M.

Publications and source records attributed to Kwesi-Maliepaard, E. M..

4 recordsLinked to original sources

bioRxiv2025

Histone methyltransferase DOT1L maintains identity and restricts cytotoxic potential of CD8 T cells

The histone methyltransferase DOT1L is emerging as a central epigenetic regulator in immune cells. Loss of DOT1L during development of CD8 T cells in vivo leads to gain of memory-features but has also been reported to compromise CD8 T cell viability and activity. Here, we determined the cell-intrinsic role of DOT1L in mature mouse CD8 T cells. After conditional deletion of Dot1L in vitro, CD8 T cells retained in vivo proliferative capacity and anti-tumor reactivity. Moreover, Dot1L knock-out CD8 T cells showed increased antigen-specific cytotoxicity towards tumor cells in vitro. Mechanistically, loss of DOT1L resulted in an altered cell-identity program with loss of T-cell and gain of NK-cell features. These transcriptional changes were mediated by loss of DOT1L methyltransferase activity in a dose-dependent manner. Our findings show that ablation of DOT1L activity in mature CD8 T cells is well-tolerated and rewires their cell identity towards the NK-cell lineage, concomitantly enhancing intrinsic cytotoxic capacity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/633937v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1641c55org.highwire.dtl.DTLVardef@1803510org.highwire.dtl.DTLVardef@1bedceorg.highwire.dtl.DTLVardef@199a6d5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDifferentiation and identity of cytotoxic T cells depend on the methyltransferase DOT1L C_LIO_LIDOT1L intrinsically limits the cytotoxic activity of mature CD8 T cells C_LIO_LIDOT1L prohibits the acquisition of NK cell features in CD8 T cells C_LIO_LIDOT1L maintains CD8 T cell identity through its catalytic activity in a dose-dependent manner C_LI

immunology↗

bioRxiv2021

SETD2 negatively regulates cell size through its catalytic activity and SRI domain

Cell size varies between cell types but is tightly regulated by cell-intrinsic and extrinsic mechanisms. Cell-size control is important for cell function and changes in cell size are frequently observed in cancer cells. Here we uncover a non-canonical role of SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription regulation, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Although most of SETD2s cellular functions have been linked to this activity, several non-histone substrates of SETD2 have recently been identified - some of which have been linked to novel functions of SETD2 beyond chromatin regulation. Using multiple, independent perturbation strategies we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that this function is dependent on the catalytic activity of SETD2 but independent of H3K36 methylation. Paradoxically, ectopic overexpression of a decoy SRI domain also increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development.

cell biology↗

bioRxiv2019

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells

Cytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naive CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

immunology↗

bioRxiv2019

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

Differentiation of naive peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Murine B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells showed aberrant differentiation and prematurely acquired plasma cell features. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L supports the repression of an anti-proliferative, plasma cell differentiation program by maintaining expression of the H3K27 methyltransferase Ezh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Our findings show that DOT1L is a central modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B cell naivety and GC B cell differentiation.

immunology↗