Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis

Dev Biol. 2007 Mar 15;303(2):814-24. doi: 10.1016/j.ydbio.2006.11.039. Epub 2006 Dec 1.

Abstract

Complete deficiency in activity-dependent neuroprotective protein (ADNP) results in neural tube closure defects and death at days 8.5-9.5 of gestation in the mouse (E8.5-9.5). To elucidate ADNP associated pathways, Affymetrix 22,690-oligonucleotide-based microarrays were used on ADNP knockout and control mouse embryos (E9) separated completely from extra embryonic tissue. Marked differences in expression profiles between ADNP-deficient embryos and ADNP-expressing embryos were discovered. Specifically, a group of dramatically up-regulated gene transcripts in the ADNP-deficient embryos were clustered into a family encoding for proteins enriched in the visceral endoderm such as apolipoproteins, cathepsins and methallotionins. In contrast, a down regulated gene cluster associated with ADNP-deficiency in the developing embryo consisted of organogenesis markers including neurogenesis (Ngfr, neurogenin1, neurod1) and heart development (Myl2). The pluripotent P19 cells were used for ADNP-chromatin-immunoprecipitation, showing direct interactions with multiple relevant gene promoters including members of the up-regulated as well as the down-regulated gene clusters. A comparison between non-differentiated and neuro-differentiated P19 cells revealed increased chromatin interaction of ADNP with chromatin from differentiated cells. These results place ADNP at a crucial point of gene regulation, repressing potential endoderm genes and enhancing genes associated with organogenesis/neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Primers / genetics
  • Embryonic Development / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Pregnancy

Substances

  • Adnp protein, mouse
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA Primers
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • heterochromatin-specific nonhistone chromosomal protein HP-1