. To learn better, keep the HAT on. Neuron. 2004 Jun 24;42(6):879-81. PubMed.

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  1. Tom Fagan has done a very nice job of calling our attention to these exceptionally important and concordant sets of results supporting Robin Holliday's original proposal for a role for epigenetic modifications in long- term memory (Holliday, 1999). Robin emphasized methylations and demethylations of CpGs in his 1999 paper; less was known at that time about alterations in gene expression associated with chromatin modifications by histone acetylases and deacetylases.

    The important phenotypic consequences of haploinsufficiency for the CREB binding protein provides a rationale for an investigation of potential roles of genetic polymorphisms, or better, of haplotype variations, in the modulation of long-term memory in human subjects.

    PS: I also want to give special thanks to Tom Fagan for having highlighted the excellent accompanying commentary by Kelsey C. Martin and YE Sun. (Kelsey Martin is my daughter!)

    References:

    . Is there an epigenetic component in long-term memory?. J Theor Biol. 1999 Oct 7;200(3):339-41. PubMed.

    View all comments by George Martin
  2. I see that many of the signs of Rubenstein-Taybi syndrome are also reported in Down's syndrome.

    The study by Branchi et al. (1) finding that overexpression of DYRK1A results in increased phosphorylation of FKHR, high levels of cyclin B1 and increased phosphorylation of CREB is of great interest.

    They report increased brain weight associated with DYRK1A overexpression, yet reduced brain weight is reported in Down's syndrome.

    Of further interest is the study by Daitoku et al. (2) finding that CREB-binding protein binds and acetylates FKHR and that Sir2 binds and deacetylates residues acetylated by CREB-binding protein.

    Do the CBP mutations reported in RTS allow for FKHR binding?

    Ironic that the CREB pathway required for learning and memory is also affected by the longevity gene, Sir2.

    Is this one reason for the mental retardation and reduced lifespan reported in Down's syndrome?

    References:

    . Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration. J Neuropathol Exp Neurol. 2004 May;63(5):429-40. PubMed.

    . Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. PubMed.

    View all comments by Mary Reid
  3. Which of the human sirtuins might target FKHR? Might we suspect SIRT2, as North et al. (1) find that it is a tubulin deacetylase.

    Hempen et al. (2) report decreased acetylated alpha-tubulin in neurofibrillary tangle-bearing neurons in AD.

    Does the overexpression of DYRK1A reported by Funakoshi et al. (3), which has resulted in chromosome missegregation, suggest that it may be a downstream effect on FKHR/SIRT2 and resultant deacetylated alpha-tubulin?

    Might we suspect a SIRT1/FKHR association? Takata and Ishikawa (4) report that SIRT1 associates with HES1 and HEY2.

    Does the fact that DYRK1A overexpression resulting in increased phosphorylated CREB also implicate this gene product in the increased presenilin-1 levels found in Down's syndrome?

    Mitsuda et al. (5) report that CREB controls expression of presenilin-1.

    I see that the Sambamurti group (6) find a CREB binding site on BACE.

    References:

    . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PubMed.

    . Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease. J Neuropathol Exp Neurol. 1996 Sep;55(9):964-72. PubMed.

    . Overexpression of the human MNB/DYRK1A gene induces formation of multinucleate cells through overduplication of the centrosome. BMC Cell Biol. 2003 Sep 10;4:12. PubMed.

    . Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Biochem Biophys Res Commun. 2003 Jan 31;301(1):250-7. PubMed.

    . Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1. J Biol Chem. 2001 Mar 30;276(13):9688-98. PubMed.

    . Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J. 2004 Jun;18(9):1034-6. PubMed.

    View all comments by Mary Reid

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