Without SIRT6, REST undergoes an "off-switch" modification, impairing its repressive activity despite increased expression, revealing why boosting REST alone is insufficient. This research opens up new avenues to target SIRT6-REST interactions for neuroprotective therapies.

Both factors are essential for healthy neuronal differentiation and neuroprotection, but as we age, SIRT6 levels decline while REST increases—yet fails to function effectively in neurodegeneration. Our findings highlight SIRT6 as the key regulator behind this paradox.

However, in pathology, when SIRT6 is absent, REST is left alone to row going in circles and becoming ineffective in its role. This study uncovers a critical link between SIRT6 and REST, two transcription factors central to brain health and aging.

I am happy to share that @molecular_guy paper is online! https://t.co/wb1n9FcpkU We can imagine REST and SIRT6 as a rowing team. In healthy brains, they work together, moving forward and protecting brain function.

First paper published! Our work defines a novel regulatory switch on neural gene expression, dependent on SIRT6 existence. It was a great opportunity to do this work under the supervision of @ToiberDebbie and the exceptional help of her lab. https://t.co/Alq0dTYI16

these are small loops that mainly contain essential housekeeping genes required for cell maintenance, preventing changes in their topology and keeping them with high expression. Congratulations to Dima, Kate and colleagues on our publication of his paper in NAR Molecular Medicine

Meanwhile, the nucleolus and central regions also expands, but to a lesser extent, causing peripheral regions to drift further apart—much like galaxies in an expanding universe. Some areas, however, become more compact,

However, as we age, the nuclear envelope weakens, allowing the chromosomes to spread out, increasing the distance between them. This expansion is more pronounced in regions that were close to the nuclear periphery, particularly near the Lamin borders.

Nuclear expansion and chromatin structure remodeling in mouse aging neurons https://t.co/sN15Wr2QeG Our DNA is typically organized within the cell nucleus like highways connected by bridges and loops, facilitating the use of the genetic information encoded within.

Metabolic changes in SIRT6-KO parallel to those seen in CSF of as Alzheimer's schizophrenia, and neuroinflammatory diseases. This preprint was led by Shai Kaluski and thanks to the huge effort of our amazing collaborators @FendtLab, Kharmeva's Gitler's, Abdu's, and Krejci labs

leading to increased production of neurotoxic metabolites, reduced serotonin and melatonin levels, and a severe neurodegenerative phenotype, with tryptophan being redirected to the kynurenine pathway.

Despite these well-established, severe effects, the molecular mechanisms behind the changes in tryptophan usage remain unknown. We discovered that the absence of SIRT6 results in the dysregulation of key rate-limiting enzymes, including TDO2 and AANAT,

Dysregulation of tryptophan catabolism is observed in aging brains and is more pronounced in neurodegenerative and psychiatric disorders, leading to detrimental effects on mood, learning, and sleep behavior. https://t.co/tPDXEaRNCX

#Postdoc Opportunity: Do you love #mechanobiology, #microscopy, and #cellmigration? Join our team at @CornellBME and @weillinstitute to investigate how cells squeeze their nucleus through tight spaces and how this affects nuclear structure and function. https://t.co/bDxRcsLHBN

This is the work of the very talented Adam Zaretsky and all our collaborators!

Our new preprint points to SIRT6 behind this paradox. REST possesses a functional switch (Me/Ac), which, in the absence of SIRT6, results in inactive REST, making the brain's attempts to overexpress it futile.

However, SIRT6 levels decrease with age and in AD, while REST exhibits an increased expression. Despite its heightened expression, REST fails to properly localize and execute its repressive functions in neurodegenerative patients, presenting a fascinating paradox.

https://t.co/Y1wkSfKfR3 Brian's development and healthy aging are tightly regulated by transcription factors SIRT6 and REST, both involved in proper neuronal differentiation and prevention of neurodegeneration. When both are present, keep a healthy brain.

Our new preprint points to SIRT6 behind this paradox. REST possesses a functional switch (Me/Ac), which, in the absence of SIRT6, results in inactive REST, making the brain's attempts to overexpress it futile. The work of the very talented Adam Zaretsky and all our collaborators

However, SIRT6 levels decrease with age and in AD, while REST exhibits an increased expression. Despite its heightened expression, REST fails to properly localize and execute its repressive functions in neurodegenerative patients, presenting a fascinating paradox.