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Research Roundup: October 9, 2020

Susanna M. Hamilton
Credit : Susanna M. Hamilton
By Broad Communications

Teaching new antimalarials new tricks, watching memories in the making, recording cell fate decisions, and more

Welcome to the October 9, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

New tricks for anti-malarials

A new study finds that promising antimalarial compounds also kill the intestinal parasite Cryptosporidium, a leading and currently incurable cause of diarrheal disease and death in children. The work was led by Boris Streipen (U. Penn), Christopher Huston (U. Vermont), and Broad Chemical Biology and Therapeutics Science Program alum Eamon Comer. Bicyclic azetidines, previously found to kill the malaria parasite in a new way, rid mice of Cryptosporidium infections after four days of once-daily treatment. Described in Science Translational Medicine and a press release, the study could help pave the way to develop urgently needed treatments.

Commit to memory

Searching for the molecular roots of memory storage in the brain, Asaf Marco (MIT), senior associate member Li-Huei Tsai in the Cell Circuits Program and of the Picower Institute for Learning and Memory at MIT, and colleagues analyzed the epigenome and three-dimensional genomic architecture of engram cells, memory-forming neurons that are altered by learning. Using a mouse model in which activated neurons are permanently tagged, they found that memory encoding increases chromatin accessibility, without gene expression changes. Memory consolidation reorganizes large chromatin segments, and memory recall leads to new promoter-enhancer interactions and altered expression of genes involved in protein synthesis in synaptic compartments. Read more in Nature Neuroscience.

Lipoprotein-based risk score for heart disease 

High levels of lipoprotein(a) can increase heart disease risk, but physicians rarely measure levels of this blood lipoprotein. Visiting student Mark Trinder (University of British Columbia), Pradeep Natarajan, associate member in the Program in Medical and Population Genetics and of Massachusetts General Hospital, and colleagues used data on 43 lipoprotein(a) gene variants from more than 370,000 UK Biobank participants to calculate a new genetic risk score that matched the predictive power of lipoprotein(a) blood measurements for heart disease risk. Such a risk score could help physicians identify high-risk patients, particularly those not flagged by traditional blood tests. Read more in JAMA Cardiology, a Mass General press release, and a tweetorial from Natarajan.

The model mice 

A hexanucleotide repeat expansion (a type of DNA mutation) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Initial studies of different transgenic mouse models of this mutation have returned conflicting results regarding survival and motor phenotypes. Institute member Kevin Eggan at the Stanley Center for Psychiatric Research, Daniel Mordes, and colleagues extensively phenotyped two independent cohorts of transgenic mice with the same mutation to evaluate their use in neurodegenerative disease research. Writing in Neuron, they report no reproducible abnormalities in survival, motor function, or neurodegeneration in either cohort.

Recording cell differentiation

To better understand the molecular programs that control early cell development, a team led by Ik Soo Kim, Jingyi Wu, Gilbert Rahme, and institute member and Epigenomics Program director Bradley Bernstein studied mouse embryonic stem cells at single-cell resolution as they developed into embryoid bodies — an organoid model composed of three germ layers. The researchers identified and validated molecular regulators of key fate decisions, and developed a new toolkit for lineage tracing of rapid differentiation processes. Read the full story in Cell Reports and check out a brief tweetorial from Rahme for more.

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