Research Roundup: July 13, 2018

Clones and blood cancer, babies' microbiomes, a step toward enhancer prediction, and more.

McGovern Institute, Justin Knight
Credit: McGovern Institute, Justin Knight

Welcome to the July 13, 2018 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Whence come the clones?

Clonal hematopoiesis — when a blood stem cell develops a mutation that lets its progeny outgrow others' — can raise people's risk of blood cancers and heart disease later in life. Following up on their 2014 study that identified the phenomenon, Po-Ru Loh, Giulio Genovese, Broad associate member Alkes Price at the Harvard T.H. Chan School of Public Health, institute member Steven McCarroll in the Stanley Center for Psychiatric Research, and colleagues reported in Nature that certain rare inherited mutations (in addition to acquired ones) can prime blood stem cells for clonal hematopoiesis, counter to previous thought. Learn more in a Harvard Medical School/Broad Institute news story.

Clonal commentary

In a Nature Medicine News & Views piece, Rob Sellar, Siddhartha Jaiswal, and institute member Benjamin Ebert from the Cancer Program comment on two new studies — one in Nature and one in Nature Medicine — aimed at the progression from clonal hematopoiesis to the development of acute myeloid leukemia. Both studies used targeted sequencing to examine DNA from individuals who went on to develop AML. The authors challenge others in the field to build on this work and design predictive models for assessing multiple outcomes of clonal hematopoiesis, such as other cancers or cardiovascular disease, and for testing therapeutic interventions.

She has her mother’s microbes

A mother's gut microbes contribute to her baby's microbiome, but only certain microbial species make the jump from mom to child. To find out why, a team of researchers including Moran Yassour, Larson Hogstrom, core institute member Ramnik Xavier in the Infectious Disease and Microbiome Program, institute director Eric Lander, and collaborators surveyed the gut microbiomes of 44 infants and their mothers in Finland, during the first three months of the infants’ lives. Their findings, published in Cell Host & Microbe, confirmed microbiome transmission from mother to child and provided snapshots of how gut microbial communities develop during a baby's early days. Learn more in this Q&A with Yassour and Hogstrom in the Broadminded Blog.

Beefing up the diet for better chemotherapy response

The chemotherapy drug methotrexate would be more effective if it were less toxic. A team led by Broad senior associate member David Sabatini, Naama Kanarek, and others from the Sabatini lab and Broad’s Cell Circuits Program performed a CRISPR-Cas9-based screen to find genes that modulate cancer cells’ response to methotrexate. Featured in Nature, the study found that the cellular process for degrading the amino acid histidine influences the sensitivity of cancer cells to methotrexate. The findings suggest that activity of a gene encoding an enzyme in this pathway could predict patients who will respond better to methotrexate treatment, and that dietary supplementation with histidine could allow lower doses of this toxic agent.

Hints of a positional code for enhancer action

Regulatory elements in noncoding DNA, like enhancers and promoters, act through transcription factors: proteins that perform a variety of roles in gene transcription. In PNAS, a team led by Sharon Grossman and Eric Lander reported that the locations of the motifs where TFs bind to enhancers fall into six distinct patterns that dovetail with the TFs functions. The patterns, the team said, may constitute a position-based regulatory code, and could help researchers learn how to predict enhancers' activity based on sequence data. Learn more in a Broad news story.

Better, faster, stronger, 3D

The Imaging Platform, including senior software engineer Allen Goodman, dives deep into version 3.0 of CellProfiler with a new paper out in PLOS Biology. CellProfiler is the team’s flagship open-source software for analyzing biological images, and the latest release has enabled automated volumetric analysis of 3D images. The update, first announced last fall on the CellProfiler blog, has also made the software faster and more user-friendly than prior versions and capable of integrating deep learning frameworks. CellProfiler is freely available for download.

Uncovering rules of regulation

In a study published in Nature Genetics, Broad Institute core member and Klarman Cell Observatory director Aviv Regev, Christine Cheng, Rachel Gate and Broad alum Chun (Jimmie) Ye at the University of California San Francisco, and colleagues optimized and used ATAC-seq to characterize how natural genetic variation in stimulated CD4+ T cells impacts variation in chromatin states and influences gene expression. They found that chromatin regions that are open for transcription in these stimulated cells co-vary with other open chromatin regions across an individual’s genome in a way that’s consistent the genome's 3D organization. These regions overlapped significantly with variants associated with autoimmune disease, suggesting that genetic variants affect chromatin accessibility in a way that influences regulatory elements, either in isolation or in concert.

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