The Mechanism of ATP-dependent Remodelers and HP1 Gene Silencing (Geeta Narlikar)

In this episode of the Epigenetics Podcast, we talked with Geeta Narlikar from UCSF about her work on chromatin remodeling, Heterochromatin Protein 1, and the molecular mechanisms that influence the genome.

The conversation starts with a pivotal paper from the early days of Dr. Narlikars research career, titled "Distinct Strategies to Make Nucleosomal DNA Accessible," focused on two ATP-dependent remodelers, BRG1 and SNF2H. Here, she notes that while both enzymes operate similarly, they generate different outputs and play distinct biological roles within the cell. The research revealed that BRG1 is more aggressive in altering nucleosome configuration, aligning with its role in transcription activation, while SNF2H showed a more refined approach in the formation of heterochromatin.

Transitioning to her work at UCSF, she emphasized the importance of collaboration and mentoring within a research group. Her focus then shifted towards the ACF ATP-dependent chromatin assembly factor, hypothesizing how ACF measures nucleosome distance—an inquiry that led to exciting insights regarding dynamic enzyme behavior. This includes findings that ACF operates not through a static ruler mechanism but rather through a kinetic mechanism, thus continuously adjusting nucleosome positioning based on DNA length during chromatin assembly.

Dr. Narlikar also delved into her studies on heterochromatin protein 1 (HP1), highlighting how HP1 recognizes methylation marks and assembles on chromatin to facilitate gene silencing. This segment of the discussion underscored her shift to studying phase separation and its implications in the organization of chromatin. Notably, her lab made significant advancements in understanding how HP1 forms phase-separated droplets, a finding that was independently corroborated by other laboratories, demonstrating the utility of collaborative scientific inquiry.

In discussing the nuances of chromatin dynamics, Dr. Narlikar also introduced her investigations into the INO80 complex, detailing its distinct mechanism for nucleosome movement compared to other remodelers. Each remodeling complex, as she elucidated, has unique catalytic capabilities while still utilizing similar biochemical foundations, highlighting the diverse regulatory roles these proteins play within cells.

References

• Racki LR, Yang JG, Naber N, Partensky PD, Acevedo A, Purcell TJ, Cooke R, Cheng Y, Narlikar GJ. The chromatin remodeller ACF acts as a dimeric motor to space nucleosomes. Nature. 2009 Dec 24;462(7276):1016-21. doi: 10.1038/nature08621. PMID: 20033039; PMCID: PMC2869534.

• Canzio D, Liao M, Naber N, Pate E, Larson A, Wu S, Marina DB, Garcia JF, Madhani HD, Cooke R, Schuck P, Cheng Y, Narlikar GJ. A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature. 2013 Apr 18;496(7445):377-81. doi: 10.1038/nature12032. Epub 2013 Mar 13. PMID: 23485968; PMCID: PMC3907283.

• Sinha KK, Gross JD, Narlikar GJ. Distortion of histone octamer core promotes nucleosome mobilization by a chromatin remodeler. Science. 2017 Jan 20;355(6322):eaaa3761. doi: 10.1126/science.aaa3761. PMID: 28104838; PMCID: PMC5656449.

• Larson AG, Elnatan D, Keenen MM, Trnka MJ, Johnston JB, Burlingame AL, Agard DA, Redding S, Narlikar GJ. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature. 2017 Jul 13;547(7662):236-240. doi: 10.1038/nature22822. Epub 2017 Jun 21. PMID: 28636604; PMCID: PMC5606208.

• Sanulli S, Trnka MJ, Dharmarajan V, Tibble RW, Pascal BD, Burlingame AL, Griffin PR, Gross JD, Narlikar GJ. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature. 2019 Nov;575(7782):390-394. doi: 10.1038/s41586-019-1669-2. Epub 2019 Oct 16. PMID: 31618757; PMCID: PMC7039410.

Related Episodes

• Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos)

• Heterochromatin Protein 1 and its Influence on the Structure of Chromatin (Serena Sanulli)

• Heterochromatin and Phase Separation (Gary Karpen)

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