HIC1 attenuates Wnt signaling by recruitment TCF-4 and β-catenin to the nuclear bodies EMBO Journal (2006)

Wnt signaling in the nucleus Wnt Off Wnt On Wnt Off (negative feedback) (Xi He et al, Development, 2006) Groucho HDAC

Wnt signaling in the nucleus - In absence of Wnt, ◦ TCF/LEF-1 - Bind constitutively to Wnt enhancers - In presence of Wnt, it can interact with corepressor, Groucho, HDAC, CBP it can interact with coactivator, β-catenin, Pygo, Bcl9, Chromatin remodeling complexes. ◦ CtBP - Transcriptional corepressor and APC-interacting protein - Binding of CtBP is correlated with the loss of histone modification (Karl Willert, Genes & Dev, 2006)

Introduction to HIC1 nuclear protein ◦ HIC1 (Hypermethylated in cancer 1) -First identified as a tumor suppressor gene frequently epigenetically silenced or deleted in different type of solid tumors (Herman JD et al, N Eng J Med, 2003) -Hic +/- mice develop malignant tumor and densely methylated in wild type allele of Hic1 promoter -CtBP associating protein and redirects CtBP to a specific set of nuclear dot-like structure called HIC1 bodies (Chen et al, Nat Genet, 2003) (Deltour et al, MCB, 2002)

What is the nuclear body ? -The nuclear body is a discrete nuclear structure -Cells typically contain 10–30 nuclear bodies per nucleus -Each nuclear body has a unique function (P. pandolfi et al, Nat cell biol, 2000)

HIC1 sequesters TCF-4 into nuclear bodies BTB/POZ : protein-protein interaction CtBP : CtBP binding domain (GLDLSKK)

CtBP is required for efficient sequestration of TCF-4

TCF-4 binds directly to HIC1 in vitro

TCF-4 C-terminal HIC1-N-term HIC1-C-term HIC1-internal ?

TCF-4 binds directly to HIC1 in vivo

HIC1 inhibits TCF/ β-catenin driven transcription 293 T cell Dimerizer regulated gene expression (Roy pollock et al, Curr opinion, 2002)

HIC1 inhibits TCF/ β-catenin driven transcription

HIC1 diverts TCF/ β-catenin from the WRP

Physiological meaning of HIC1 Regulating maximum limit of gene expression? CtBP interacts with many of HATs HDAC activity?