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!)

View all comments by George M. Martin

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:
(1) Journal of Neuropathology and Experimental Neurology: Vol. 63, No. 5, pp. 429–440. Transgenic...  Read more

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:
(1) Journal of Neuropathology and Experimental Neurology: Vol. 63, No. 5, pp. 429–440. Transgenic Mouse In Vivo Library of Human Down Syndrome Critical Abstract

(2) Proc Natl Acad Sci U S A. 2004 Jun 25 [Epub ahead of print] Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Abstract

View all comments by Mary Reid

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:
(1) North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003...  Read more

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:
(1) North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. Abstract

(2) J Neuropathol Exp Neurol. 1996 Sep;55(9):964-72. Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease. Hempen B, Brion JP. Abstract

(3) BMC Cell Biol. 2003 Sep 10;4(1):12. Overexpression of the human MNB/DYRK1A gene induces formation of multinucleate cells through overduplication of the centrosome. Funakoshi E, Hori T, Haraguchi T, Hiraoka Y, Kudoh J, Shimizu N, Ito F. Abstract

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

(5) J Biol Chem. 2001 Mar 30;276(13):9688-98. Epub 2000 Dec 14. Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1. Mitsuda N, Ohkubo N, Tamatani M, Lee YD, Taniguchi M, Namikawa K, Kiyama H, Yamaguchi A, Sato N, Sakata K, Ogihara T, Vitek MP, Tohyama M. Abstract

(6) FASEB J. 2004 Jun;18(9):1034-6. Epub 2004 Apr 01. Gene structure and organization of the human beta-secretase (BACE) promoter. Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK. Abstract

View all comments by Mary Reid