Insights on the regulation of the MLL/SET1 family histone methyltransferases

Luo, Sha; Ayoub, Alex; Cho, Uhn‐Soo; Dou, Yali

doi:10.1016/j.bbagrm.2020.194561

Cited by 24 publications

(29 citation statements)

References 89 publications

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“…Set methyltransferases usually work together in multi-proteins ( Bergamin and Couture, 2016 ; Sha et al, 2020 ). ASH2L is one of the important non-catalytic cofactors of set-containing proteins and required for the trimethylation of H3K4.…”

Section: Resultsmentioning

confidence: 99%

Smyd1 Orchestrates Early Heart Development Through Positive and Negative Gene Regulation

Wang

Schwartz

Liu

et al. 2021

Front. Cell Dev. Biol.

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SET and MYND domain-containing protein 1 (Smyd1) is a striated muscle-specific histone methyltransferase. Our previous work demonstrated that deletion of Smyd1 in either cardiomyocytes or the outflow tract (OFT) resulted in embryonic lethality at E9.5, with cardiac structural defects such as truncation of the OFT and right ventricle and impaired expansion and proliferation of the second heart field (SHF). The cardiac phenotype was accompanied by the downregulation of ISL LIM Homeobox 1 (Isl1) and upregulation of atrial natriuretic factor (ANF). However, the mechanisms of Smyd1 regulating Isl1 and ANF during embryonic heart development remain to be elucidated. Here, we employed various biochemical and molecular biological approaches including chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR), pGL3 fluorescence reporter system, and co-immunoprecipitation (CoIP) and found that Smyd1 interacted with absent small homeotic-2-like protein (ASH2L) and activated the promoter of Isl1 by trimethylating H3K4. We also found that Smyd1 associated with HDAC to repress ANF expression using trichostatin A (TSA), a deacetylase inhibitor. In conclusion, Smyd1 participates in early heart development by upregulating the expression of Isl1 and downregulating the expression of ANF.

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Section: Resultsmentioning

confidence: 99%

Smyd1 Orchestrates Early Heart Development Through Positive and Negative Gene Regulation

Wang

Schwartz

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…11,12 The highly conserved class 2 lysine methyltransferases (KTM2) comprises the mixed lineage leukaemia family (MLL1, MLL2, MLL3, MLL4, MLL5) and SET1A/SET1B enzymes, and are responsible for deposition of most of the H3K4 methylation marks associated with transcription. 13 With the exception of MLL5, the catalytic activity of the KMT2s is dependent on the assembly of further adaptor proteins. The so called WRAD complex consists of WD repeat-containing protein 5 (WDR5), DPY30, absent, small or homeotic-2 like (ASH2L) and retinoblastoma binding protein 5 (RBBP5).…”

Section: Introductionmentioning

confidence: 99%

“…The reaction mixture was diluted with water and extracted 3x with DCM. The crude 9H) ppm 13. C NMR (126 MHz, CD2Cl2) δ = 165.9, 145.5, 142.3, 139.8, 136.5, 130.8, 130.1, 126.8, 120.4, 117.6, 113.8, 81.1, 55.0, 51.0, 46.1, 28.3 ppm.…”

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confidence: 99%

“…The structures of the synthesized compounds were verified by1 H-and13 C NMR, and mass spectrometry (ESI/ MALDI). Purity of the final compounds(254, 260 and 280 nm >95%) was determined by analytical HPLC.…”

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confidence: 99%

“…Commercially available VHL ligand 1 Hydrochloride was used for the degrader molecules 8a-j and 17a-g, while the VHL ligand for the negative control 20 and 21 was obtained analog to Buckley and van Molle 34 . 1 H NMR and13 C NMR spectra were measured in DMSO-d6, MeOD, CD2Cl2 or CDCl3 on a Bruker DPX250, AV300, AV400, AV500, DPX600, AV700 or AV800 spectrometer. Chemical shifts δ are reported in parts per million (ppm).…”

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confidence: 99%

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Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Doelle

Adhikari

Kraemer

et al. 2021

Preprint

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Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

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