Everything Everywhere All at the Liau Lab

新年快樂！

Happy belated (Lunar) New Year from the Liau Lab! It’s been a really busy past year for us, filled with both science and, well…not-science.

We are all Michelle Yeoh <3

From apple picking to ice skating, we’ve had lots of fun over the past year:

Apple picking, or as the kids like to say, Pick Apple-ing.

Breakfast for dinner at our favorite local IHOP.

Ice skating at the Fenway rink. Brian is a very “down-to-earth” PI.

Enjoying some soondubu at Kaju!

Olivia educates the group on grass jelly desserts at MeetFresh.

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Fun aside, we’ve also been hard at work. In fact, 2022-2023 has really been the year of the Liau Lab—well, at least publishing-wise ;) In case you missed our recent scientific work, here’s a quick summary of our papers from the past year. Note: this is continuing off of our previous blog post—go check that out for our recent publications on molecular glue degraders and more!

Lamina-Inducible Methylation and Hi-C (LIMe-Hi-C)

Chemical biology meets 3D genomics! We developed a new approach to simultaneously look at chromosome conformation, DNA methylation, and lamina positioning. Through this, we found and subsequently characterized intriguing Polycomb-marked subcompartments!

DNMT3A base editor scanning

The lab’s first base editor screen, using an innovative reporter approach to study a nonessential gene! We leveraged an endogenous methylation activity reporter to map sequence-activity relationships across DNMT3A. Following up our screen results, we found a noncanonical DNA binding role for the PWWP histone reader domain. What’s more is that our screening strategy can be applied toward other chromatin regulators!

CRISPR-suppressor scanning

Our lab’s official protocol for CRISPR-suppressor scanning is out in Current Protocols! If you’re interested in mapping drug-protein interactions and identifying resistance mutations, you’ll be interested in checking this out.

DNMT1 activity-based CRISPR scanning

CRISPR screens for allostery? Taking advantage of decitabine, an activity-based DNA methyltransferase inhibitor that is nearly identical to the cytosine substrate, we applied CRISPR-suppressor scanning to look for mutations impacting allostery. We found some interesting ones causing DNMT1 hyperactivation. This paper also has some updated and improved analytical tools for analyzing tiling CRISPR screening data.

This paper is currently accepted in principle and we don’t have the pdf yet, but please enjoy our graphical abstract :3

PRC2 drug-addiction scanning

CRISPR screening a whole complex! We used CRISPR-suppressor scanning to systematically mutate the three core members of the PRC2 complex, discovering mutations that confer drug addiction. These pointed toward a model where lymphoma cells need to be in a “Goldilocks” state—too much or too little H3K27me3 is bad.

We had some fun creating art related to some of these studies, though unfortunately they weren’t selected by the journals for the cover/feature. Well, even if journals don’t appreciate our art, hopefully our blog readers will!

Nick, Allison, and Shelby collaborated to make this artistic representation of our LIMe-HiC method. The lime cross-section represents the nucleus, and the red represents GpC methylation.

Nick made this design representing DNMT3A base editor scanning. The pins represent loss-of-function mutations scattered across DNMT3A, and the compass is an homage to base editing.

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This past year also saw some new faces arriving in our group. We welcomed the skilled organic chemist, Dr. Stefan Harry, as a joint postdoc with the Bar-Peled lab at MGH. Additionally, we said hi to Tobias Hansen, a visiting graduate student from the University of Copenhagen!

Dr. Stefan Harry

Tobias Hansen

We also welcomed three (count ‘em, yep, we’re popular) new CCB graduate students to the lab:

Calvin Hu

Marc Anthony Zepeda

Idris Barakat

In more bittersweet news, we said goodbye to our longtime lab administrator Rebecca. We’re sad to see her go, but luckily she still works in the department so we can say hi :) On the bright side, we welcomed Lizzy Swenson as our new lab administrator, and have had a great time getting to know her!

Rebecca Stillo

Lizzy Swenson

Continuing with bittersweet departures, our lab has experienced some turnover in our researchers as well. Earlier in the year, we had three talented scientists move on to their next positions:

Pallavi, our first biologist postdoc and a stellar scientist, is now a Senior Scientist at Merck. Pallavi launched the protein biochemistry side of the lab and has provided invaluable expertise to numerous projects. More recently, she led our lab’s study applying CRISPR-suppressor scanning to investigate molecular glues.

Jiaming, a superb synthetic organic chemist postdoc, recently returned to California as a Senior Scientist at Ideaya Biosciences. He served as a mentor and wellspring of expertise for many during his time here, and synthesized a huge number of vital compounds, leaving a lasting mark on our lab (and our freezers).

Sam, a talented research assistant, is now attending medical school at the Cleveland Clinic, Case Western Reserve University! Sam was instrumental in biochemically characterizing DNMT1 mutants and also contributed to numerous other projects.

Check out these videos from Jiaming and Sam’s farewell party, by the way:

You may have seen our last blog post, but we also had four talented graduate students defend (Ally, Kevin, Allison, and Amanda). (*suppresses sobbing*)

Kevin Ngan, Ph.D. Kevin is now working at Tessera Therapeutics.

Allison Siegenfeld, Ph.D. Allison is now doing a postdoc in Prof. Karen Adelman’s lab at HMS.

Amanda Waterbury, Ph.D. Amanda is continuing in our lab as a postdoc for the near future.

Ally Freedy, Ph.D. Ally is now finishing the M.D. part of her M.D.-Ph.D. training at HMS.

With so much going on, 2023 has arrived sooner than any of us expected. But you know what? We have even more cooking, science-wise. Stay on the lookout for the YEAR OF THE LIAU LAB, PART 2!

Publications, Preprints, and PQEs—Oh My!

It’s a bird!… It’s a plane!… no… It’s the latest—

LIAU LAB BLOG POST !!!

Did you miss us? It’s been a hectic year for us, but we are so excited to share the work we’ve been up to. We’ve had a lot of things in the works and 2022 is shaping out to be the year that we unleash the flood on the scientific community. Ready or not, here we come!

Keen followers of our website might have noticed some changes recently. We’ve revamped our website, for starters, and what’s more, we’ve dropped some new publications. Let’s take a quick stroll through them…

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But first of all we have an important announcement to make. The big man himself has finally joined the twittersphere! Help us get him to 1,000 followers (or at least to another fun number before that)!

Please like + subscribe! <3

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Now back to what you’re here for. Without further ado, here are our lab’s peer-reviewed publications from the past year! Click on the pictures to go to the journal site.

The exciting sequel to 2019’s Park et al. paper! We synthesized improved cycloheximide derivatives and collaborated with the Shao lab to perform cryo-EM characterization. A multidisciplinary study spearheaded by Yumi and Eileen.

Drug resistance sounds scary but it’s actually been a driving force for biological discovery. Ally wrote an insightful review on the history of drug resistance alleles and their utility for science moving forward.

Our New Year’s present to the chemical biology community in the form of CRISPR-suppressor scanning with molecular glue degraders. Sounds like a sticky problem, right? But it was no match for Pallavi, Kevin, and the rest of the team!

But wait, there’s more! We have not one, not two, not even three, but four additional stories out on bioRxiv as of today. They’ll be out in journals sometime soon* but if you’re dying to take a look, click on the images below!

*soon: sometime in the next decade, probably (you know how peer review is)

Finally, we are proud to say that all three of our CCB grad students this year passed their PQEs (preliminary qualifying exams) with flying colors! We celebrated with some champagne, though not without some technical difficulties…

Congratulations to Megan, Olivia, and Nicholas!

Anyway, that’s all for today! Keep your eyes peeled for more exciting Liau Lab work just around the corner….!

Happy Holidays from the Liau Lab!

Season’s greetings from your favorite chemical epigenomics lab ;)

This New Year’s Eve, we in the Liau Lab hope that you, your family, and your friends continue to enjoy your holidays and have a great start to the new year! It’s been a year full of challenges and new experiences for all of us, and we owe so much to the healthcare workers, public health officials, and everyone else who has worked to control the pandemic. We are thankful for have had the opportunity to continue our research this past year and beyond :)

Like many others, our lab has been divided into shifts: a morning shift and an evening shift. Luckily for us, we all got to choose the shift that more or less best suits our sleep schedules (or, um, lack thereof). Unsurprisingly, there’s a bit of a difference in the types of people that self-sorted into the two shifts…

Spot-on assessment from Emma. Please note the Comic Sans.

Fig. 1: Representative screenshot illustrating significant morning shift wholesomeness (p < 0.05).

Fig. 2: Representative screenshot illustrating evening shift degeneracy. Results are, of course, not significant.

To help us get accommodate more lab members while still staying at a safe density, our lab was fortunate to annex some new lab space. Take a look!

Thank you to the lab members that graciously accepted banishme— temporary relocation to our annex spaces!

Zoom fatigue? What’s that?

Of course, in an era of distancing and virtual meetings, we’ve been trying to figure out ways to stay connected to each other. Beyond zoom coffee hours, some lab members organized a virtual social over Thanksgiving weekend, where we got to battle for glory in some online games.

Hui Si Kwok, master of deception. Turns out postdoc hands can be used for passaging cells or wiping out your crewmates.

Playing codenames!

Though it was a challenge to adapt our annual holiday party to Zoom, no pandemic was going to get in the way of celebrating another year in Liau Lab history. Thanks to Ceejay for planning this event, and to Emma and others for stepping up to make the annual Year in Review presentation…

it’s fine

Virtual partygoers!

The boss posing with his holiday gift from the lab.

As is traditional, we had a little competition for lab members. This year, Ceejay organized a rousing game of “Brian Bingo”: the game where you predict things Brian will do over Zoom and assemble your own dream bingo board out of them. Although no one got a real bingo, Shelby came the closest. Here’s a look at her winning board:

Red indicates correctly predicted Brian-isms. 5 plus the free space, not bad!

So there you have it! It’s been a long year, and we’ve had our ups and downs, but whether we’re resting or working, we’re trying to do our best to prepare ourselves for the new year.

We’ll leave you with some mouthwatering desserts from Allison’s kitchen:

Allison’s pecan pie.

Allison’s (vegan) pumpkin cheesecake.

Trust us, we’ll need the sugar to get us pumped for the new year. It’s truly been an experience living through 2020, but we’re excited to see what 2021 brings. Until next time, and stay safe!

Ally and Kevin present at the Broad!

This morning the lab had the exciting opportunity to present at the Broad Institute’s Cell Circuits and Epigenomics meeting! Ally and Kevin served as our representatives, talking about their work studying LSD1 and DNMT1, respectively.

Ally talks about our lab’s work studying the lysine demethylase, LSD1. If you haven’t already, check out our paper in Nature Chemical Biology!

Kevin fields questions from an eager scientist after his talk.

Many thanks to Cell Circuits and Epigenomics for including us in their community and letting us share some of our exciting findings. Until next time!

Let’s hear some applause for our speakers!

A new chapter for the Liau Lab

With our group practically doubling in size over the past year, it was about time for us to take a new group photo. Many thanks to Beverly Fu from the Balskus lab for helping us with the shoot! After many failed attempts marred by blinking eyes and blocked faces, we finally got a good shot, full of smiles and Brian’s signature "boss” pose.

If you follow us on twitter or have been obsessively checking our website (who could blame you?) you may have noticed some updates over the past few months on our publications page. That’s right – the lab’s first two papers are out in Angewandte Chemie International Edition and Nature Chemical Biology. Click on the paper titles above to check out these awesome works, which really showcase two of the major and ongoing focuses of our lab.

The LSD1 project was (and still is) a huge, interdisciplinary endeavor that required the coordinated efforts of many members of our lab (as well as collaborators) in a diverse array of fields. Here, the core members of the LSD1 team celebrate a hard-won success. Congratulations!

In the midst of these exciting events, we’ve unfortunately had to say goodbye to our wonderful laboratory manager, Larry Valles, who has moved on to serve as a Junior Operations Manager for Immunology, Microbiology, and Genetics at Harvard Medical School. While we’ll miss him, we’re also happy that he has accepted this great opportunity and wish him the best! We’ll always remember Larry for supporting us through the trials and tribulations of research.

Larry (a.k.a. “molecule”), purveyor of doughnuts and bagels and harbinger of diabetes.

In a bittersweet way, 2019 is proving to be a big year of change for the Liau lab. We’re looking forward to everything the future has to offer, and we can’t wait to share more of our scientific and non-scientific exploits with the world!