A novel mouse model of syndactyly: The role of CtBP1/2 in limb organogenesis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22695
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Yakushiji-Kaminatsui Nayuta 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (70565316)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: エピジェネティクス / 四肢形成 / 合指症 / CtBP

Outline of Final Research Achievements

It is known that CtBP1/2 act as co-repressor of Polycomb group (PcG) proteins, however, its function in limb organogenesis is largely unclear. We first generated Ctbp1/2-dKO mice and found that distal and terminal phalanges were completely fused. This specific phenotype resembles Syndactyly type VI, in which the molecular mechanism is unknown. Therefore, in this research project, we aimed to elucidate the molecular mechanism of Syndactyly from the viewpoint of epigenetic regulation by CtBP1/2 and PcG proteins. By using analyses of transcriptome and chromatin profiling, we showed increased levels of H3K27ac and RING1B across potential limb enhancers under the lack of CtBP1/2. We further found that most PcG-target genes tended to be upregulated in the dKO distal limb bud, correlating with increased level of H3K27ac at the promoters. These suggest that CtBP1/2 act as repressor via regulating the H3K27ac levels across promoters and potential limb enhancers during limb organogenesis.

Free Research Field

発生生物学

Academic Significance and Societal Importance of the Research Achievements

合指症は生まれつき隣り合った指が癒合した状態であり、外科手術による治療が一般的である。遺伝子のミスセンス突然変異や、DNA配列の重複が発症原因として報告されているものもあるが、多くのタイプではその原因は不明のままである。また、クロマチン抑制因子であるポリコム複合体と、そのコリプレッサーとして作用するCtBP1/2が四肢疾患の発症原因として報告された事例もない。したがって、本研究成果は合指症の発症機序を明らかにするだけでなく、エピゲノムをターゲットとした新しい出生前診断・治療法開発への貢献が大いに期待されるものである。