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Single-Cell Atlas Simultaneously Maps 3D Genome Architecture and DNA Methylation

Published

1 week ago

July 24, 2026

Single-Cell Atlas Simultaneously Maps 3D Genome Architecture and DNA Methylation

Scientists at the Salk Institute and the Arc Institute, along with their collaborators, unveiled the first body-wide single-cell atlas of two major epigenetic systems: three-dimensional genome folding and DNA methylation, measured simultaneously in the same cells.

The atlas spans 86,689 cells from 16 human tissues, revealing 35 major cell types and 206 subtypes, and is freely available online. The work is part of the National Institutes of Health’s 4D Nucleome (NIH 4DN) program, which aims to understand how the genome is organized in space and time to regulate gene expression in health and disease.

Because the two epigenetic layers were measured together, the researchers could compare what each layer says about a cell’s identity. And while often the two pictures agree, they found that sometimes they do not.

The Salk paper “Human body single-cell atlas of 3D genome organization and DNA methylation” was published alongside five other NIH 4DN papers in Science, and three others in Science Advances.

The Human Genome Project, completed in 2003, produced a linear read of the three billion DNA letters in the human body. But the letters alone don’t explain how a single genome produces hundreds of different cell types. That information lives in the epigenome in the form of chemical modifications and structural folds layered on top of the DNA sequence, where they can switch genes “on” and “off” in patterns specific to each cell type.

Caption: Salk scientists Jingtian Zhou (left), Jesse Dixon (center), and Joseph Ecker (right) profiled 86,689 cells across 16 human tissues, linking cell-type-specific epigenetic features to disease risk and revealing that a cell’s 3D genome and DNA methylation don’t always tell the same story. [Salk Institute]

Two of the most consequential epigenetic features are 1) DNA methylation, where small chemical groups called methyl groups are attached to specific DNA bases, and 2) 3D genome organization, where intricate loops, folds, and compartments bring distant stretches of DNA into contact. Both influence gene expression, but they had never been measured together in single cells across the human body.

“There has been an appreciation for trying to understand, at the individual cell level, how the genome is organized, so that we can get a better idea of how genetic variants impact disease,” said co-corresponding author Joseph Ecker, PhD, a professor and Salk International Council Chair in Genetics at Salk and a Howard Hughes Medical Institute investigator. “Some cell types may be more vulnerable than others to genetic variants, because the genome is organized differently in different cell types—and whether a variant matters can depend on that organization.”

Why is noncoding DNA relevant in disease?

Most disease-associated genetic variants fall in the noncoding regions of the genome. That has made it difficult to figure out how a variant contributes to disease, which cell type it acts in, and what gene it ultimately affects.

The new atlas identifies more than 1.36 million differentially methylated regions and 283,606 differential chromatin loops across the human body’s cell types, using tissues from the heart, brain, lungs, stomach, skin, and more. When the researchers overlaid genetic variants known to raise disease risk, specific pairings emerged like variants for blood-glucose regulation concentrated in endocrine cells, atrial fibrillation variants in heart muscle cells, balding variants in skin fibroblasts, and bipolar disorder and schizophrenia variants in excitatory and inhibitory neurons.

“A lot of the genetic variation that predisposes someone to disease is in noncoding parts of the genome,” said co-corresponding author Jesse Dixon, MD, PhD, associate professor and Helen McLoraine Developmental Chair at Salk. “By adding in the 3D genome aspect, we can potentially bridge that gap—connecting noncoding variations with the genes they affect in specific cells and tissues.”

glial cells — Microglia, illustration. Researchers from the New York Genome Center and Columbia University used the atlas’ cross-tissue methylation data to show that a substantial fraction of the brain’s resident immune cells (microglia) are replaced by cells resembling blood monocytes between roughly ages 50 and 75. The finding challenges the long-held view that microglia persist from embryonic development throughout the life span. [Artur Plawgo/Getty Images]

What happens when two epigenetic lenses disagree?

One of the study’s most surprising findings is that DNA methylation and 3D genome structure don’t always tell the same story about a cell. In skeletal muscle, the team found fibers that look like mature, differentiated muscle cells by their 3D genome folding, but still carry the methylation signature of muscle stem cells. The reverse almost never happens. The most plausible explanation, they explained, is that these cells are caught mid-differentiation, with 3D architecture updating first and methylation catching up.

Similar mismatches appeared in Schwann cells of the peripheral nervous system and in placental trophoblasts. The pattern suggests that different epigenetic features update on different time scales during cell state transitions—a finding that could reshape how researchers define “cell type” in adult tissues and how they track cells moving between states in disease.

The atlas also revises a long-standing assumption about “non-CG methylation,” an unusual form of methylation previously thought to be largely confined to brain cells and stem cells. The study shows that it carries cell-identity information across many human tissues, including muscle, pancreas, and immune cell types, at lower but biologically meaningful levels.

“The inconsistency between modalities may be further used to determine what cell populations are switching between each other in adult tissues and diseases, which could, for example, expand our understanding of cancer cell dynamics,” said co-first and co-corresponding author Jingtian Zhou, PhD, a former graduate researcher in Ecker’s lab who now leads his own lab at the Arc Institute.

A public resource for scientists and artificial intelligence

To make the atlas broadly usable, the team built an interactive web browser that lets researchers visualize DNA methylation and 3D chromatin contacts across every tissue, cell type, and subtype in the study. The underlying data, including 195 billion methylation measurements and 18 billion chromatin contacts, are freely available.

The resource arrives as artificial intelligence tools are increasingly used to predict the functional impact of genetic variants. Atlases like this one can provide the labeled, cell-type-resolved training data that models need to make accurate predictions—a bottleneck that has historically limited the field.

For example, in a companion paper in the same issue of Science, a study led by Bing Ren, PhD, from the New York Genome Center and Columbia University used the atlas’ cross-tissue methylation data to show that a substantial fraction of the brain’s resident immune cells, called microglia, are replaced by cells resembling blood monocytes between roughly ages 50 and 75. The finding challenges the long-held view that microglia persist from embryonic development throughout the life span.

“DNA methylation patterns are specific to each cell type and analogous to a cellular barcode,” said Ren, who also co-authored the Salk-led study. “The comprehensive cross-tissue DNA methylation atlases show that the aging microglia in the human hippocampus more closely match the monocytes from peripheral blood than microglia from young adults, providing a crucial clue for the biological identity of these cells.”

The NIH 4D Nucleome consortium, of which this study is a part, aims to extend this kind of mapping into the fourth dimension: time. A 4D understanding of the genome—how its structure and chemistry change as cells develop, age, and respond to disease—remains a major goal, and the cross-tissue atlas provides reference scaffolding that future time-course studies will build on.

Along with scientists from the Salk Institute and Arc Institute, investigators from the University of California, San Diego, Columbia University, New York Genome Center, University of California, Los Angeles, Harvard, Henan University in China, Vanderbilt University, Stanford University, Broad Institute, University of Sheffield in the U.K., Yale, University of Florida, University of Freiburg in Germany, University of Graz in Austria, and Nanchang University in China; and Chongyuan Luo also contributed to the Science paper.

The post Single-Cell Atlas Simultaneously Maps 3D Genome Architecture and DNA Methylation appeared first on GEN – Genetic Engineering and Biotechnology News.

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Biotech leaders call for streamlining of INDs as FDA’s Trialblazer rolls out

Published

3 hours ago

August 3, 2026

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The FDA’s new investigational new drug pilot program—one part of HHS’s broader clinical trial modernization initiatives—has lofty goals to expedite first-in-human trials of novel drugs, but experts say it won’t tip the scales much on its own.

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5 companies advancing ATTR assets in the wake of Wainua’s fail

Published

3 hours ago

August 3, 2026

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The Phase 3 failure of AstraZeneca and Ionis Pharmaceuticals’ antisense therapy in transthyretin amyloid cardiomyopathy last month left the space reeling—and readjusting. BioSpace looks at five contenders and where they currently stand.

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StockWatch: Capricor Plunges as FDA Panel, Staff Question Effectiveness of Lead Candidate Deramiocel

Published

7 hours ago

August 3, 2026

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After seeing its lead candidate rejected by the FDA last year, Capricor Therapeutics (Nasdaq: CAPR) is hoping for a better outcome for its resubmitted biologics license application (BLA) for its lead pipeline candidate Deramiocel, a cell therapy indicated as a treatment for cardiomyopathy in Duchenne muscular dystrophy (DMD).

That hope appeared less likely than ever as the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee on Wednesday recommended against agency approval of Deramiocel, concluding in a 9-3 vote with no abstentions that the available evidence from the Phase III HOPE-3 trial (NCT05126758) did not “provide substantial evidence of effectiveness” for Deramiocel as a treatment for cardiomyopathy in Duchenne muscular dystrophy (DMD).

The advisory committee vote is likely to influence how the FDA acts on the resubmitted BLA for Deramiocel, with the agency having set an August 22 target decision date under the Prescription Drug User Fee Act (PDUFA). The FDA typically (but not always) heeds the advice of its advisory committees or “adcomms,” which in turn typically (but not always) heed the evaluations of agency staff.

Deramiocel is an allogeneic cardiosphere-derived cell (CDC) therapy candidate. CDCs are designed to act by secreting exosomes that target macrophages and alter their expression profile to adopt a healing rather than pro-inflammatory phenotype.

According to Capricor, preclinical and clinical studies have shown Deramiocel to preserve cardiac and skeletal muscle function in muscular dystrophies such as DMD by exerting strong immunomodulatory and anti-fibrotic activity.

Negative FDA evaluation

FDA reviewers paved the road to Deramiocel’s poor reception from the adcomm on July 27 with a negative evaluation of the resubmitted BLA. Their assessment concluded that data submitted to the FDA from HOPE-3 and the earlier Phase II HOPE-2 trial (NCT03406780) “does not provide substantial evidence of effectiveness for Deramiocel in DMD”—though Capricor’s indication for Deramiocel is specifically cardiomyopathy in DMD.

The unnamed FDA staffers took issue with:

Whether Deramiocel achieved HOPE-3’s primary and secondary endpoints.
The hypersensitivity shown by 42% of Deramiocel patients vs. 15% of placebo patients;

Capricor’s failing to submit to the agency an updated statistical analysis plan (SAP) for review before it resubmitted its BLA for Deramiocel in February.

Capricor declared HOPE-3 a successful trial in December, citing as a statistically significant benefit the reported 54% slowing of skeletal muscle disease progression on the primary endpoint, Performance of the Upper Limb version 2.0 (PUL 2.0) percentage change from baseline in the 105-patient intent-to-treat (ITT) population with evaluable PUL v2.0 assessments at 12 months. Capricor also reported a 91% slowing of progression measured by left ventricular ejection fraction (LVEF) in the 83-patient ITT population with centrally reviewed and evaluable cardiac MRI LVEF assessments at 12 months.

The FDA, however, says HOPE-3 can only be deemed a success after the company made changes to its SAP that included modifications to the primary and key secondary endpoint definitions, its analytical methods; and the data imputation strategy for intercurrent events.

“Although the applicant provides justifications for these changes, FDA does not agree that the scientific rationale for those changes was supported and considers the changes unwarranted based on the study’s design, powering, and original statistical assumptions,” the FDA staffers contended.

The reviewers also alleged that the distinctive adverse event profiles seen between Deramiocel and placebo patients “raises the possibility that treatment assignment could be inferred even under formal blinding conditions.”

“This risk of functional unblinding,” they added, “was further extended by the open-label period of HOPE-3, during which additional treatment-related data accumulated and may have made treatment assignment more apparent.”

Capricor answers back

Capricor answered back the same day. CEO Linda Marbán, PhD, told Reuters she was “completely shocked at how they decided to review and analyze this data,” while the company issued a statement faulting the FDA for relying on an “obsolete” analysis: “Our results are governed by the final analysis plan, SAP version 3.0, which was finalized prior to unblinding.”

“It is critical to understand that the post-hoc analyses in the FDA’s briefing materials rely on SAP version 1.1, an unsigned incomplete internal draft which became obsolete with the addition of cohort B and did not include content specifically requested by FDA,” Capricor explained. “We believe Deramiocel offers a meaningful treatment option for boys and young men living with Duchenne, who continue to face a significant unmet medical need.”

The company sought to back up that contention on Wednesday, when it released updated data from HOPE-3 that were published in The Lancet. The updated data showed Deramiocel to have improved cardiac and skeletal muscle function in Phase I–II studies of DMD, and also found that deramiocel could slow muscle weakening in boys and young men with advanced DMD, and may also slow heart damage in those who already have heart muscle disease.

But at 12 months of follow-up, Deramiocel’s performance on the study’s key secondary endpoint of LVEF “did not reach statistical significance, although the difference [favored] Deramiocel,” researchers reported, as the Deramiocel group vs. placebo showed a least-squares mean ranked change in LVEF of 57·47 ranks compared with 45·82 for placebo.

“These findings reinforce deramiocel as a safe, effective, and promising therapy for individuals living with DMD. Longer follow-up is needed to establish durability, long-term safety, and effects on clinically important cardiac outcomes,” the research team from Capricor and its clinical partners wrote in the study.

They added: “A 54% reduction in mean skeletal-muscle disease progression over 12 months, if sustained, would be equivalent to delaying approximately 1 year of untreated progression over 2 years.”

Investors unpersuaded

Capricor’s responses during the week failed to persuade investors. They responded to the negative FDA staff briefing on Deramiocel with a sharp sell-off that sent the company’s shares nosediving 64.5% to $7.00, from $19.70 at the close of trading July 24. The decline reached 85% when Capricor shares hit a 52-week low of $2.97 early Thursday.

After the downgrades and second stock plunge of the week, however, Capricor investors began to “buy the dip” and sent the company’s shares partially rebounding to $4.19 on Thursday (a 36% one-day slide) and $3.85 at Friday’s closing bell, down 8%. Overall for the week, Capricor’s stock suffered an 80% one-week decline.

News of the FDA adcomm vote led to downgrades of Capricor stock and severe 12-month price target downgrades by at least six investment firms:

Piper Sandler (Edward Tenthoff)—From “Overweight” to “Neutral,” all but wiping out its price target 97%, from $58 to $2.
Cantor Fitzgerald (Kristen Kluska)—From “Overweight” to “Neutral,” eviscerating its price target 94%, from $62 to $3.50.
Ladenburg Thalmann (Aydin Huseynov, MD)—From “Buy” to “Neutral,” no price target announced.
Maxim Group (Jason McCarthy, PhD)—From “Buy” to “Hold,” no price target announced.
C. Wainwright (Joseph Pantginis, PhD)—From “Buy” to “Neutral,” removing its $60 price target reiterated in May.
Oppenheimer (Leland Gershell, MD, PhD)—From “Outperform” to “Perform,” removing its $54 price target reiterated in March.

“The briefing documents raise many more concerns versus what we originally were anticipating, putting Capricor in a tough situation” for the adcomm meeting, Kluska said Monday in remarks reported by Reuters.

The six firms joined three others that lowered their ratings on Capricor shares earlier in the week:

Alliance Global Partners (Matthew Venezia)—From “Buy” to “Neutral,” chopping its price target 86%, from $51 to $7 on Tuesday.
Riley Financial (Madison El-Saadi, PhD)—From “Buy” to “Neutral,” slashing its price target 84% from $63 to $10 on Monday.
Roth Capital Partners (Boobalan Pachaiyappan, PhD)—From “Buy” to “Neutral,” slicing its price target 82% from $38 to $7 on Monday.

MapLight data divides investors, analysts

Investors and the Wall Street analysts who cover their favorite companies sometimes don’t see eye to eye. That was apparent this past week when MapLight Therapeutics (Nasdaq: MPLT) shares went on something of a roller-coaster ride, as mixed clinical results for its lead drug in a mid-stage trial in schizophrenia sent the stock nosediving on investor fears—until reassurances from analysts reversed the slide and sent those shares back in the positive direction.

The up-and-down week ended with MapLight shares sliding 64%.

MapLight’s wayward week started on July 27 when the company released data from its 307-patient Phase II ZEPHYR trial (NCT07038876) assessing its lead pipeline candidate ML-007C-MA in adults with an acute exacerbation of schizophrenia. ML-007C-MA is an oral, extended-release, fixed-dose combination of the M₁/M₄ muscarinic agonist candidate ML-007, co-formulated with a peripherally acting anticholinergic.

MapLight trumpeted what it termed positive results from ZEPHYR, though the data appeared to be more mixed: On the positive side, the 210/3 mg twice-daily (BID) dose of ML-007C-MA showed statistically significant and clinically meaningful reduction in its Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at Week 5 in a In the modified intent-to-treat (mITT) population, with an effect size of 0.37 and a least squares mean 4.5-point improvement vs. placebo (p=0.015).

However, the 330/6 mg once-daily (QD) dose of ML-007C-MA did not achieve statistical significance on the primary endpoint, even as it showed an effect size of 0.23 and a 2.8-point improvement over placebo (p=0.110)—as well as separation on CGI-S (p=0.036), PANSS positive Marder factor (p=0.045), and Readiness for Discharge Questionnaire (p=0.027), and numerical separation on other endpoints.

That result investors scurrying to sell off their MapLight shares, since it raised questions about whether ML-007C-MA could effectively with Cobenfy^® (xanomeline and trospium chloride), the schizophrenia drug marketed by Bristol Myers Squibb (BMS; NYSE: BMY). Cobenfy, which won FDA approval in 2024, showed larger PANSS reductions of 8.4 and 9.6 points in a pair of Phase III trials compared with placebo.

Cobenfy generated $119 million in product revenues in the first half of this year, nearly double (up 92%) from January–June 2025), in addition to $155 million during all of last year.

The BID dose also showed robust and clinically meaningful improvement in cognitive performance, based on the pre-specified secondary endpoint assessed via the Cogstate battery in participants with baseline cognitive impairment (effect size=0.51; 0.44 points vs. placebo; p=0.041). But the cognitive benefit did not show correlation with the change in PANSS score, something that MapLight said suggested that “the effect was independent of, and not secondary to, improvement in psychotic symptoms.”

“We are very encouraged by these results, which show that ML-007C-MA delivered clinically meaningful antipsychotic efficacy alongside a favorable tolerability profile designed to translate into real-world use,” Chris Kroeger, MD, MapLight’s co-founder and CEO, said in a statement.

Encouraged enough, Kroeger added, that MapLight plans to discuss a path forward for ML-007C-MA in schizophrenia, including the design of a Phase III trial, at an End-of-Phase II (EOP2) meeting with FDA officials. Data from that trial, combined with results from ZEPHYR, are intended to support an initial New Drug Application (NDA) submission for the drug.

Investors sharply disagreed with MapLight’s optimism, sending the company’s shares plummeting 73% on July 27, from $36.56 to $9.90. But several analysts questioned the wisdom of investors selling off shares on a single PANSS number.

“The PANSS score is but one component of what might drive success from a commercial point of view,” cautioned Sumant Kulkarni, a senior analyst covering biotechnology with Canaccord Genuity, wrote in a research note. “At the same time, we need to see more data from additional trials on safety and efficacy.”

That data could come, he continued, from the Phase II VISTA trial (NCT06887192) assessing ML-007C-MA as a treatment for hallucinations and delusions associated with Alzheimer’s disease psychosis, a potentially larger market for the drug.

However, Kulkarni cut Canaccord Genuity’s peak-year 2037 sales forecast for ML-007C-MA by more than half in schizophrenia, from approximately $1 billion to approximately $400 million. He also shrunk by one-third his firm’s peak sales forecast for ML-007C-MA in ADP, from $3 billion to $2 billion, and lowered ***HOW its forecast of MapLight’s operating expenses.

As a result of these changes, Kulkarni cut Canaccord Genuity’s 12-month price target on MapLight shares 44%, from $43 to $24.

“Although [ML-007C-MA] did not meet the Street’s upside expectations, there are still several positives to consider,” Jefferies equity analyst Andrew Tsai wrote Friday. He said ZEPHYR was still successful enough as a pivotal Phase II trial to count as one of two positive Phase II or III trials needed for FDA approval. And twice daily ML-007C-MA showed competitive adverse event percentages among patients compared to Cobenfy, he added, citing:

Constipation—9% for ML-007C-MA vs. 13–21% for Cobenfy.
Nausea—29% vs. 19%.
Vomiting—13% vs. 9–16% for Cobenfy.

By mid-week, investors appeared to take the analyst commentary to heart. MapLight shares rebounded, climbing 24% to $12.31 on Tuesday, then jumped another 22% to $15.02 Wednesday. The rest of the week didn’t look as good for MapLight, however, as its shares fell about 7% to $14.03 Thursday and dropped another 7% Friday, finishing the week at $13.03.

Leaders & laggards

Novo Nordisk (Nasdaq Copenhagen: NOVO-B) shares slumped 8% from DKK 330.90 ($51.03) to DKK 306.50 ($47.27) Friday, while its American Depositary Shares (Nasdaq: NVO) skidded 9% from $51.61 to $47.08, after the cardiometabolic drug giant acknowledged that its once-monthly 15 mg dose of ziltivekimab failed the Phase III ZEUS trial (NCT05021835) assessing the IL-6 inhibitor vs. placebo in reducing the risk of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke. Ziltivekimab failed to translate reductions in cardiovascular inflammation into fewer major cardiovascular events, Novo Nordisk said. Overall rates of adverse events (AEs) and serious AEs in ziltivekimab patients were similar to those seen with placebo. A higher proportion of people treated with ziltivekimab had serious infections compared to placebo—a finding consistent with targeting IL-6 inhibition, according to the company—while no difference in all-cause mortality was seen.
Replimune Group (Nasdaq: REPL) shares more than doubled, jumping 107% from $5.41 to $11.20 Friday, the day after the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee sided with the company by voting 10-3 that the results from the Phase I/II IGNYTE trial (NCT03767348) were evaluable and clinically meaningful. Repligen is seeking FDA approval of its third biologics license application (BLA) for RP1 (vusolimogene oderparepvec, a genetically engineered oncolytic viral immunotherapy, in combination with nivolumab, the programmed death-1 (PD-1) immune checkpoint inhibitor marketed by Bristol Myers Squibb (NYSE: BMY) as Opdivo^®, as a treatment for advanced melanoma in patients who have progressed on prior anti-PD-1 therapy. “We are encouraged by today’s outcome and would like to thank the committee for its thoughtful discussion of the IGNYTE data,” Repligen CEO Sushil Patel, PhD, said in a statement. Cantor Fitzgerald analyst Li Watsek upgraded Replimune shares from “Neutral” to “Overweight,” with no price target on the stock.