Diverse functions of PHD fingers of the MLL/KMT2 subfamily

Ali, Mohsin; Hom, Robert A.; Blakeslee, Weston W.; Ikenouye, Larissa; Kutateladze, Tatiana G.

doi:10.1016/j.bbamcr.2013.11.016

Cited by 70 publications

(63 citation statements)

References 33 publications

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“…We also found upregulated expression of several Plant Homeo Domain (PHD) zinc finger proteins including Bromodomain and PHD Finger-containing protein 1 BRPF1, PHF13, PHF23, and Inhibitor of Growth family member 2 (ING2) [24], [25]. These proteins function as histone readers recognizingH3K4 methylation and recruit histone acetyl-transferase complexes involved p53/TP53cell cycle arrest (GADD45ACDKN2D) and DNA repair (RAD9A, MSH6, BRCA1 associated RING domain 1 BARD1, REPIN1, and POLE3) ( Figure 6B ) [22].…”

Section: Resultsmentioning

confidence: 90%

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

et al. 2014

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Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial RegistrationClinicalTrials.gov NCT01365065

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Section: Resultsmentioning

confidence: 90%

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

et al. 2014

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“…The third PHD domain in MLL1 is important for H3K4me3 binding and MLL1 recruitment to target sites in the Hox locus 34. Other PHD domains within SETD1/MLL may also interact with H3K4me3 but remain to be further characterized 35. The ability of SETD1/MLL to sample promoters and bind H3K4me3 may be involved in the maintenance of this mark at active genes.…”

Section: Active Histone Modificationsmentioning

confidence: 99%

The interplay of histone modifications – writers that read

2015

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Histones are subject to a vast array of posttranslational modifications including acetylation, methylation, phosphorylation, and ubiquitylation. The writers of these modifications play important roles in normal development and their mutation or misregulation is linked with both genetic disorders and various cancers. Readers of these marks contain protein domains that allow their recruitment to chromatin. Interestingly, writers often contain domains which can read chromatin marks, allowing the reinforcement of modifications through a positive feedback loop or inhibition of their activity by other modifications. We discuss how such positive reinforcement can result in chromatin states that are robust and can be epigenetically maintained through cell division. We describe the implications of these regulatory systems in relation to modifications including H3K4me3, H3K79me3, and H3K36me3 that are associated with active genes and H3K27me3 and H3K9me3 that have been linked to transcriptional repression. We also review the crosstalk between active and repressive modifications, illustrated by the interplay between the Polycomb and Trithorax histone-modifying proteins, and discuss how this may be important in defining gene expression states during development.

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“…The MLL1 methyltransferase has four PHDs, where the third can bind to H3K4me3 (Chang et al 2010;Wang et al 2010). The third PHD of MLL2 and the single PHD of MLL5 also both recognize this same histone mark (Ali et al 2013(Ali et al , 2014Lemak et al 2013). This is likely related to Spp1 function in homologous yeast COMPASS (see above) for efficient propagation of this critical histone mark.…”

Section: Selection Of Specific Ptm-carrying Nucleosomes By Modifier Ementioning

confidence: 99%

Histone target selection within chromatin: an exemplary case of teamwork

2014

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Histone modifiers like acetyltransferases, methyltransferases, and demethylases are critical regulators of most DNA-based nuclear processes, de facto controlling cell cycle progression and cell fate. These enzymes perform very precise post-translational modifications on specific histone residues, which in turn are recognized by different effector modules/proteins. We now have a better understanding of how these enzymes exhibit such specificity. As they often reside in multisubunit complexes, they use associated factors to target their substrates within chromatin structure and select specific histone mark-bearing nucleosomes. In this review, we cover the current understanding of how histone modifiers select their histone targets. We also explain how different experimental approaches can lead to conflicting results about the histone specificity and function of these enzymes.

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Diverse functions of PHD fingers of the MLL/KMT2 subfamily

Cited by 70 publications

References 33 publications

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

The interplay of histone modifications – writers that read

Histone target selection within chromatin: an exemplary case of teamwork

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