Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility

Area of Science:

• Epigenetics
• Molecular Biology
• Immunology

Background:

• Ten-eleven translocation (TET) enzymes modify DNA by oxidizing 5-methylcytosine.
• This oxidation is a key step in DNA demethylation and epigenetic regulation.
• TET enzymes play roles in various cellular processes, including development and differentiation.

Purpose of the Study:

• To investigate the role of TET enzymes in early B cell development.
• To determine the impact of Tet2 and Tet3 loss on B cell transition and Igκ locus regulation.
• To elucidate the mechanism by which TET proteins influence chromatin accessibility and enhancer function.

Main Methods:

• Utilized a mouse model with concomitant loss of Tet2 and Tet3 at the early B cell stage.
• Analyzed B cell development, Irf4 expression, and Igκ locus transcription/rearrangement.
• Assessed CpG methylation and chromatin accessibility at Igκ enhancers.
• Performed rescue experiments by re-expressing the Tet2 catalytic domain.

Main Results:

• Concomitant loss of Tet2 and Tet3 blocked pro- to pre-B cell transition in bone marrow.
• Tet2/3 deficiency decreased Irf4 expression and impaired Igκ locus germline transcription and rearrangement.
• Tet2/3-deficient pro-B cells exhibited increased CpG methylation and decreased chromatin accessibility at Igκ enhancers.
• Re-expression of Tet2 restored Igκ enhancer demethylation and chromatin accessibility.

Conclusions:

• TET proteins are essential for proper B cell development and Igκ locus regulation.
• TET proteins cooperate with transcription factors to control chromatin accessibility and enhancer function through DNA modification.
• Modulation of DNA modification status by TET enzymes is critical for B cell differentiation.