Dataset Information

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies.

ABSTRACT: Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

SUBMITTER: Staehle HF

PROVIDER: S-EPMC8699298 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies.

Staehle Hans Felix HF Pahl Heike Luise HL Jutzi Jonas Samuel JS

Biomolecules 20211220 12

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emergin ...[more]

PMID: 34944554

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Project description:BACKGROUND: The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function. RESULTS: We describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded beta-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups. CONCLUSION: We give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.

Dataset Information

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies.

Publications

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies.

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