Epigenetic Editing: Turning Genes On and Off Without Cutting DNA

The Promise of Editing Without Cutting

Every cell in your body carries the same three-billion-letter DNA sequence, yet a neuron looks and behaves nothing like a liver cell. The difference is not in the letters themselves but in which letters are being read. A vast regulatory layer — chemical tags on DNA, structural modifications to the proteins that package it, and small RNA molecules that fine-tune its expression — determines which genes are active and which are silent in any given cell at any given time. This regulatory layer is the epigenome, and epigenetic editing is the emerging discipline that seeks to rewrite it on demand.

The concept sounds almost too elegant: instead of cutting DNA with molecular scissors and risking permanent, sometimes unpredictable mutations, you simply tell a gene to be quiet — or to speak up. No double-strand breaks, no insertions or deletions, no reshuffling of the genetic code. Just a targeted chemical instruction that changes gene expression while leaving the underlying sequence untouched.

As of late 2025, this idea has moved from academic curiosity to clinical reality. In November 2024, Tune Therapeutics received approval in New Zealand to dose the first human patient with an epigenetic editor — a milestone that marks the beginning of an entirely new class of genetic medicine. Meanwhile, Chroma Medicine, co-founded by gene editing pioneer David Liu, is advancing its own epigenetic editing platform toward the clinic. The race to control gene expression without altering DNA has officially begun.

Understanding Epigenetics: The Software Layer of the Genome

Before we can understand epigenetic editing, we need to understand what the epigenome actually is and how it works. If DNA is the hardware — the fixed instruction set encoded in every cell — then epigenetics is the software that determines which instructions are executed.

DNA Methylation

The most studied epigenetic mark is DNA methylation — the addition of a small methyl group (CH3) to cytosine bases in the DNA, typically at CpG dinucleotides (places where a cytosine sits next to a guanine). When a gene's promoter region — the stretch of DNA that serves as its "on switch" — accumulates methyl groups, the gene is silenced. The methyl tags physically block transcription factors from binding and recruit proteins that compact the surrounding chromatin into a closed, inaccessible state.

DNA methylation is maintained by a family of enzymes called DNA methyltransferases (DNMTs). DNMT1 copies existing methylation patterns during cell division, ensuring that a silenced gene stays silenced in daughter cells. DNMT3A and DNMT3B establish new methylation marks. Conversely, TET enzymes (TET1, TET2, TET3) remove methyl groups through a multi-step oxidation process, reactivating silenced genes.

This is a critical point: methylation is not permanent. It is a reversible chemical tag that can be added or removed by the cell's own enzymatic machinery.

Histone Modification

DNA does not float freely in the nucleus. It is wrapped around protein spools called histones, forming a structure called chromatin. The tails of histone proteins are decorated with a dizzying array of chemical modifications — acetylation, methylation, phosphorylation, ubiquitination, and more — that collectively determine whether a stretch of DNA is accessible for transcription or packed away in silence.

Histone acetylation, catalyzed by enzymes called histone acetyltransferases (HATs, such as p300/CBP), generally opens chromatin and activates gene expression. Histone deacetylases (HDACs) remove acetyl groups and promote gene silencing. Histone methylation is more context-dependent: methylation of histone H3 at lysine 4 (H3K4me3) is associated with active genes, while methylation at lysine 27 (H3K27me3) or lysine 9 (H3K9me3) signals gene silencing.

Why Epigenetics Matters for Disease

Epigenetic dysregulation underlies a staggering range of human diseases. In cancer, tumor suppressor genes are often silenced by aberrant DNA methylation — not mutated, just turned off. In chronic viral infections like hepatitis B (HBV), viral DNA hijacks the host's epigenetic machinery to persist in a quasi-dormant state called covalently closed circular DNA (cccDNA). In neurological disorders like Fragile X syndrome, a critical gene (FMR1) is silenced by excessive methylation of its promoter. In Angelman syndrome, the maternal copy of UBE3A is silenced by an antisense transcript, and the paternal copy is epigenetically imprinted.

In all of these cases, the DNA sequence is intact. The gene is present, functional, and ready to work — it has simply been told to be quiet. Epigenetic editing aims to change that instruction.

How Epigenetic Editing Works: dCas9 and Its Effector Partners

The core technology behind most epigenetic editing platforms is a modified version of the CRISPR system. Standard CRISPR-Cas9 uses a guide RNA to direct the Cas9 protein to a specific genomic location, where Cas9 cuts both strands of DNA. Epigenetic editing replaces the cutting with chemical modification.

The Dead Cas9 (dCas9) Platform

The key innovation is dCas9 — a catalytically "dead" version of the Cas9 protein in which both nuclease domains (RuvC and HNH) have been disabled by point mutations. dCas9 retains its ability to be guided to any genomic location by a guide RNA, but it cannot cut DNA. It simply sits there, a programmable DNA-binding platform waiting to be given a job.

That job comes from an effector domain — an enzyme or protein fragment fused to dCas9 that performs a specific epigenetic modification at the target site. The choice of effector determines whether a gene is silenced or activated:

For gene silencing:

• DNMT3A (or its catalytic domain): Deposits methyl groups on CpG sites in the target gene's promoter, establishing stable silencing
• KRAB (Kruppel-associated box): Recruits the KAP1/TRIM28 complex, which in turn recruits histone deacetylases and histone methyltransferases (SETDB1), creating a repressive chromatin environment marked by H3K9me3
• DNMT3A + DNMT3L + KRAB combinations: Multiple repressive domains fused together for durable, multi-layered silencing

For gene activation:

• p300 (histone acetyltransferase): Deposits acetyl groups on histone H3 at lysine 27 (H3K27ac), opening chromatin and activating transcription
• TET1 (or its catalytic domain): Removes methyl groups from CpG sites, de-repressing silenced genes
• VP64, p65, Rta (VPR): Transcriptional activation domains that recruit the cell's transcription machinery to the target gene
• CRISPRa synergistic activators (SunTag, SAM): Engineered systems that amplify transcriptional activation by recruiting multiple copies of activation domains

Making Silencing Durable

One of the most important advances in epigenetic editing has been achieving durable gene silencing that persists long after the editing machinery is gone. Early experiments with dCas9-KRAB showed transient repression — the gene turned back on within days of the editor being cleared from the cell. This was a significant limitation: if the effect is only temporary, you would need repeated dosing, which complicates clinical development enormously.

The breakthrough came from combining multiple repressive mechanisms. Angelo Bhatt's group at UCSF, in collaboration with Jonathan Weissman, demonstrated in 2021 and 2022 that fusing dCas9 to both KRAB and DNMT3A (and sometimes DNMT3L, which enhances DNMT3A activity) could establish silencing that persisted for months in dividing cells — and was maintained through cell division. The key insight was that DNA methylation, once established at the right density and in the right context, is self-reinforcing: DNMT1 copies it during replication, and the methylated state recruits additional repressive machinery that maintains the closed chromatin configuration.

As Tune Therapeutics CEO Michael Ehlers described it in a 2024 interview: "We are not just temporarily turning a gene off. We are writing an epigenetic program that the cell itself maintains, the way the cell naturally maintains the silencing of thousands of genes throughout your lifetime."

Tune Therapeutics: The First Epigenetic Editor in Human Trials

Tune Therapeutics, founded in 2021 and headquartered in Durham, North Carolina, has become the first company to bring an epigenetic editing therapy into human clinical trials. The company was co-founded by Charles Gersbach of Duke University, a pioneer in the development of epigenetic effector proteins, along with Fyodor Urnov of the Innovative Genomics Institute and Michael Ehlers, a former Biogen executive who serves as CEO.

The HBV Program: TUNE-401

Tune's lead program targets chronic hepatitis B virus (HBV) infection, a disease that affects an estimated 296 million people worldwide and causes nearly 900,000 deaths annually from cirrhosis and liver cancer. Current antiviral therapies suppress HBV replication but cannot cure the infection because they fail to eliminate the virus's covalently closed circular DNA (cccDNA) — a minichromosome that persists in the nucleus of infected liver cells and serves as the template for viral reactivation.

TUNE-401 uses a lipid nanoparticle to deliver mRNA encoding a dCas9-based epigenetic editor that targets the cccDNA of HBV. Rather than trying to destroy the viral DNA (which risks off-target cuts to the host genome), TUNE-401 silences it by depositing repressive epigenetic marks — effectively telling the viral genes to shut down permanently. The cccDNA remains physically present but transcriptionally inert, like a book that has been permanently shelved and locked away.

In November 2024, Tune Therapeutics received approval from Medsafe, New Zealand's medicines regulatory authority, to initiate a Phase 1 clinical trial of TUNE-401 in patients with chronic HBV. This represents the first time any epigenetic editing therapy has been administered to a human being — a landmark moment comparable to the first CRISPR-Cas9 clinical trial in 2019.

"This is a watershed moment for the field of epigenetic editing," Gersbach said in a Tune Therapeutics press release. "We are demonstrating that you can durably silence disease-causing genes in patients without making a single permanent change to their DNA."

Beyond HBV

Tune's pipeline extends beyond viral diseases. The company has disclosed preclinical programs in:

• Chronic pain: Silencing the SCN9A gene, which encodes the Nav1.7 sodium channel implicated in pain signaling, as a potential non-opioid analgesic
• Oncology: Silencing oncogenes or reactivating tumor suppressor genes that have been epigenetically silenced in cancer
• Inflammatory diseases: Modulating expression of key inflammatory mediators

The company raised $300 million in a Series C round in 2024, valuing it as one of the most well-funded private biotech companies in the gene editing space.

Chroma Medicine: David Liu's Epigenetic Editing Company

If Tune Therapeutics represents one pole of the epigenetic editing landscape, Chroma Medicine represents another. Co-founded in 2021 by David Liu — the Harvard chemist who invented both base editing and prime editing — Chroma is developing a suite of epigenetic editing tools that emphasize gene activation as well as gene silencing.

Liu's involvement lends Chroma significant scientific credibility. His lab at the Broad Institute has been at the forefront of programmable epigenetic modification, publishing foundational work on using engineered proteins to write and erase specific epigenetic marks with high precision. As Liu noted in a 2023 Nature Biotechnology interview: "Epigenetic editing is arguably the most natural form of gene editing — you are working with the same chemical language that cells already use to regulate themselves."

Chroma's Platform

Chroma Medicine's platform encompasses both gene silencing and gene activation capabilities:

• Gene silencing (Chroma-S): Using engineered methyltransferase domains to deposit durable CpG methylation at target promoters
• Gene activation (Chroma-A): Using demethylases and transcriptional activators to turn on silenced genes

The company has disclosed preclinical work in liver-directed programs, neurological disorders, and immunology, though it has been more guarded about specific targets than Tune. Chroma raised $235 million in a Series B round in 2023, bringing its total funding to over $350 million.

The Gene Activation Frontier

One of the most exciting developments in the field — and an area where Chroma has been particularly active — is epigenetic gene activation: turning genes on rather than off. In January 2026, researchers at the Broad Institute (including members of Liu's group) published a landmark paper demonstrating robust, durable gene activation in vivo using engineered CRISPRa systems delivered by lipid nanoparticles. The study showed that targeted removal of DNA methylation combined with deposition of activating histone marks could stably upregulate gene expression in mouse liver cells for months after a single treatment.

This is a conceptual breakthrough because it means epigenetic editing is not limited to silencing — it can also rescue genes that disease has wrongly turned off. Conditions like Angelman syndrome (where the paternal UBE3A allele is epigenetically silenced), Fragile X syndrome (where FMR1 is silenced by CGG repeat-driven methylation), and certain cancers (where tumor suppressors like p16/CDKN2A are methylated into silence) could potentially be treated by reactivating the dormant gene rather than replacing it.

Advantages Over Traditional Gene Editing

Why pursue epigenetic editing when CRISPR-Cas9, base editing, and prime editing already exist and have proven clinical utility? The answer lies in a set of unique advantages that make epigenetic editing the preferred approach for certain categories of disease.

No Double-Strand Breaks

The most obvious advantage is safety. Standard CRISPR-Cas9 creates double-strand breaks (DSBs), which the cell must repair. This repair process is imperfect — it can introduce insertions, deletions, and chromosomal rearrangements. In rare cases, DSBs at the wrong location can activate oncogenes or disable tumor suppressors, raising concerns about cancer risk. Base editing and prime editing reduce these risks substantially but still involve nicking one strand of DNA and occasionally produce unintended byproducts.

Epigenetic editing with dCas9 creates no breaks whatsoever. The DNA backbone remains physically intact. This eliminates an entire category of safety concerns and is particularly important for applications in sensitive tissues like the brain, where even rare mutagenic events could have catastrophic consequences.

Reversibility

A change to the DNA sequence is permanent. An A-to-G base edit cannot be spontaneously undone by the cell. While permanence is often desirable (you want a corrective edit to last a lifetime), it also means that any mistake is permanent. If an off-target edit occurs, it will persist in the patient's genome forever.

Epigenetic modifications, by contrast, are inherently reversible. The same enzymatic machinery that writes methylation marks (DNMTs) and erases them (TETs) is present in every cell. If an epigenetic edit produces an undesirable effect, it is theoretically possible to reverse it by delivering the opposing effector. This built-in reversibility provides a safety margin that no other form of gene editing can match.

As Fyodor Urnov, co-founder of Tune Therapeutics and a leading figure in the gene editing field, has stated: "The reversibility of epigenetic editing is not a weakness — it is a feature. It gives us a pharmacological control that permanent DNA editing simply cannot offer."

No Off-Target Mutations

Because dCas9 does not cut DNA, off-target binding events do not produce mutations. A dCas9 molecule that lands on the wrong genomic location will deposit an epigenetic mark at that site, which may have transient transcriptional consequences, but it will not create a permanent, heritable change to the genome. Moreover, off-target epigenetic marks deposited at low efficiency tend to be erased by the cell's normal epigenetic maintenance machinery, providing a natural correction mechanism.

Targeting Gain-of-Function and Dominant Diseases

Many diseases are caused by genes that produce too much of a protein or produce it in the wrong place. Cancer driven by overactive oncogenes, repeat expansion disorders that produce toxic RNA, and viral infections that depend on persistent gene expression all fall into this category. For these diseases, the goal is not to correct a mutation but to reduce or eliminate expression of the offending gene. Epigenetic silencing is ideally suited to this task — it does not require knowing the exact mutation, only the identity of the gene to be silenced.

Feature	CRISPR-Cas9	Base Editing	Prime Editing	Epigenetic Editing
Mechanism	Double-strand break	Chemical base conversion	Reverse transcription	Epigenetic mark deposition
DNA breaks	Yes (DSB)	Nicks one strand	Nicks one strand	None
Permanence	Permanent	Permanent	Permanent	Durable but reversible
Off-target risk	Indels at off-targets	Bystander edits	Low indels	Transient off-target marks
Can silence genes	Via disruption	Limited	Limited	Yes (primary strength)
Can activate genes	No	No	No	Yes (CRISPRa)
Can correct mutations	Via HDR (low efficiency)	Transition mutations	All 12 substitutions + indels	No (modulates expression only)
Clinical stage	Approved (Casgevy)	Phase 1/2	Preclinical	Phase 1 (Tune, 2024)

Applications Across Disease Categories

Cancer

Epigenetic dysregulation is a hallmark of cancer. Tumor suppressor genes are frequently silenced by aberrant promoter methylation, while oncogenes may be activated by loss of repressive marks. Epigenetic editing offers two complementary strategies:

• Silencing oncogenes: Using dCas9-DNMT3A/KRAB to methylate and repress overactive cancer-driving genes such as MYC, KRAS, or BCL2
• Reactivating tumor suppressors: Using dCas9-TET1/p300 to demethylate and reactivate genes like p16/CDKN2A, BRCA1, or MLH1 that have been epigenetically silenced in tumors

This approach could complement existing cancer immunotherapies. Preclinical studies have shown that epigenetic reactivation of silenced immune checkpoint ligands or antigen presentation genes in tumor cells can restore the ability of the immune system to recognize and destroy cancer.

Viral Diseases

Beyond HBV, epigenetic silencing has therapeutic potential against other persistent viral infections. HIV proviral DNA integrates into the host genome and can be epigenetically silenced to establish latency — but it can also reactivate. Researchers have explored using epigenetic editors to lock HIV proviral DNA in a permanently silenced state, preventing viral rebound without antiretroviral therapy. Similar approaches are being investigated for herpesviruses (HSV, CMV, EBV) that establish latent infections driven by epigenetically regulated gene expression programs.

Neurological Disorders

The brain is arguably the most compelling target for epigenetic editing because of the limited regenerative capacity of neurons and the consequent danger of DNA-cutting approaches. Several neurological conditions are driven by epigenetic dysregulation:

• Fragile X syndrome: The leading inherited cause of intellectual disability, caused by silencing of the FMR1 gene due to CGG trinucleotide repeat expansion and subsequent promoter hypermethylation. Epigenetic activation of the silenced FMR1 allele could restore production of the FMRP protein and potentially reverse symptoms.
• Angelman syndrome: Caused by loss of function of the maternal UBE3A gene. The paternal copy is intact but epigenetically silenced by an antisense transcript (UBE3A-ATS). Silencing UBE3A-ATS with an epigenetic editor would de-repress the paternal UBE3A, restoring protein production. Multiple groups, including researchers at UNC Chapel Hill, are pursuing this approach.
• Chronic pain: Nav1.7, encoded by the SCN9A gene, is a sodium channel critical for pain signaling. Individuals with loss-of-function mutations in SCN9A are congenitally insensitive to pain but otherwise healthy. Epigenetically silencing SCN9A in dorsal root ganglia neurons could provide long-lasting pain relief without the addiction risks of opioids — a transformative prospect for the chronic pain field.

Repeat Expansion Disorders

Diseases caused by trinucleotide repeat expansions — including Huntington's disease (HTT), myotonic dystrophy type 1 (DMPK), and spinocerebellar ataxias — often produce toxic RNA or protein products from the expanded allele. Epigenetic silencing of the expanded allele while preserving expression of the normal allele (allele-specific silencing) is an active area of research. This approach exploits the fact that epigenetic editors can be directed to sequences flanking the repeat expansion that differ between the two alleles, selectively silencing only the disease-causing copy.

Challenges and Limitations

Epigenetic editing is not without its challenges, and intellectual honesty demands that we address them directly.

Durability vs. Reversibility: The Paradox

The field faces a fundamental tension. For therapeutic applications, you want epigenetic changes to be durable — lasting months, years, or a lifetime after a single treatment. But durability and reversibility are inherently in tension. A mark that is easily reversed by endogenous enzymes may not persist long enough to be therapeutic. A mark that is deeply entrenched may be difficult to reverse if something goes wrong.

Current evidence suggests that properly established DNA methylation — particularly when combined with repressive histone marks — can persist for the lifetime of a non-dividing cell (such as a neuron) and can be maintained through cell division by DNMT1 in dividing cells. But long-term durability data in humans does not yet exist. The Tune Therapeutics HBV trial and subsequent studies will provide critical answers.

Delivery Remains a Bottleneck

Like all gene editing modalities, epigenetic editing faces the delivery challenge: how do you get the editing machinery into the right cells in a living human? Most current approaches use lipid nanoparticles (LNPs) to deliver mRNA encoding the dCas9-effector fusion protein and the guide RNA. LNPs naturally traffic to the liver, which is why HBV is a logical first clinical target. But reaching other organs — the brain, the heart, skeletal muscle, the lungs — requires advances in LNP engineering, alternative delivery vehicles, or direct administration routes (intrathecal injection for the CNS, for example).

The size of the payload is also a concern. A dCas9 protein fused to one or more effector domains is large — often exceeding the packaging capacity of adeno-associated virus (AAV) vectors that are commonly used for in vivo gene therapy. Split-intein approaches (dividing the protein across two AAV vectors that reassemble inside the cell) are being explored but add complexity.

Specificity of Epigenetic Marks

Not all epigenetic marks are created equal, and the consequences of off-target epigenetic modification are not yet fully understood. While off-target methylation is unlikely to cause the acute safety problems associated with off-target DNA cuts, persistent silencing of the wrong gene could have subtle, long-term consequences. The field needs better tools for mapping genome-wide epigenetic changes after editing, and long-term follow-up studies in animal models and eventually in patients.

Regulatory Pathway

Epigenetic editors occupy an ambiguous regulatory space. They do not alter the DNA sequence, which means they may not technically qualify as "gene therapies" under some regulatory frameworks. The FDA and EMA have not yet issued specific guidance on epigenetic editing products. Regulatory clarity will be essential as more programs advance toward the clinic.

The Competitive Landscape: Who Is Building What

Beyond Tune Therapeutics and Chroma Medicine, a growing number of companies and academic groups are working on epigenetic editing technologies:

• Epicrispr Biotechnologies (Cambridge, MA): Developing next-generation epigenetic editors with improved specificity and durability, using novel effector domain architectures
• Navega Therapeutics (San Diego, CA): Focused specifically on epigenetic silencing for chronic pain via SCN9A repression in the dorsal root ganglia
• Neumora Therapeutics: Exploring epigenetic approaches alongside its broader neuroscience pipeline
• Academic laboratories: Groups at Duke University (Gersbach), UCSF (Bhatt/Weissman), the Broad Institute (Liu), MIT (Bhatt, formerly), and the Innovative Genomics Institute (Doudna/Urnov) continue to publish foundational advances in the field

The intellectual property landscape is complex, with overlapping patents on dCas9 fusion proteins, specific effector domain combinations, and delivery approaches. As the field matures, IP disputes similar to the historic CRISPR patent battle between the Broad Institute and UC Berkeley may emerge.

Future Outlook: Where Epigenetic Editing Is Headed

The next five years will be decisive for epigenetic editing. Several developments bear watching:

Clinical data from Tune's HBV trial will provide the first evidence of whether epigenetic editing works in humans — whether it can durably silence a disease gene, whether the effect persists, and whether it is safe. Results from the Phase 1 trial are expected in 2026 and will shape the trajectory of the entire field.

Expansion beyond the liver is the next frontier. Advances in lipid nanoparticle engineering, including targeting ligands that direct LNPs to non-liver tissues, will determine how broadly epigenetic editing can be applied. The brain remains the highest-value, hardest-to-reach target.

Gene activation therapies will emerge as the next wave. Silencing a gene is conceptually simpler than activating one (you are adding "off" signals rather than trying to orchestrate the complex "on" machinery), but the January 2026 demonstration of durable in vivo gene activation suggests that CRISPRa-based therapies are closer than many expected.

Combination approaches — using epigenetic editing alongside DNA-cutting CRISPR, base editing, or prime editing — may prove more effective than any single modality. For example, you might use CRISPR to correct a mutation in one allele while epigenetically silencing a dominant-negative allele, or combine epigenetic silencing of a viral gene with base editing to introduce escape-proof mutations.

Diagnostic and research applications should not be overlooked. Epigenetic editors are already invaluable tools for basic research, allowing scientists to dissect the function of individual regulatory elements by turning them on and off at will. This "epigenome engineering" approach is accelerating our understanding of gene regulation, development, and disease in ways that complement genome-wide association studies and single-cell sequencing.

The Bottom Line

Epigenetic editing represents a philosophical shift in genetic medicine. For two decades, the dominant paradigm has been to fix the genome — to find the mutation and correct it. Epigenetic editing asks a different question: what if the sequence is fine, but the instructions for reading it are wrong? What if, instead of rewriting the book, we just need to change which chapters are being read?

The answer, increasingly, is that this is not only possible but therapeutically powerful. Tune Therapeutics has placed the first bet, bringing an epigenetic editor into human trials for HBV. Chroma Medicine and others are not far behind. The technology offers a unique combination of durability, reversibility, and safety that no other form of gene editing can match — not because it is better in every situation, but because it solves problems that DNA cutting cannot.

We are witnessing the birth of a new branch of genetic medicine. The genes do not need to be changed. They just need to be told what to do.

Sources & Further Reading

• Tune Therapeutics announces first patient dosed in epigenetic editing clinical trial — Company press release, November 2024
• Chroma Medicine raises $235M Series B for epigenetic editing platform — Chroma Medicine corporate communications, 2023
• Nuñez, J.K. et al. "Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing." Cell 184, 2503-2519 (2021). — Foundational paper on durable epigenetic silencing with CRISPR
• Amabile, A. et al. "Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing." Cell 167, 219-232 (2016). — Early demonstration of persistent epigenetic silencing
• Liu, X.S. et al. "Editing DNA methylation in the mammalian genome." Cell 167, 233-247 (2016). — David Liu's group on targeted methylation editing
• Thakore, P.I. et al. "Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements." Nature Methods 12, 1143-1149 (2015). — Gersbach lab's foundational work on CRISPRi-based epigenetic editing
• World Health Organization: Hepatitis B Fact Sheet — Global HBV disease burden statistics
• Yeo, N.C. et al. "An enhanced CRISPR repressor for targeted mammalian gene regulation." Nature Methods 15, 611-616 (2018). — Improved KRAB-dCas9 architectures
• Nakamura, M. et al. "CRISPR technologies for precise epigenome editing." Nature Cell Biology 23, 11-22 (2021). — Comprehensive review of epigenetic editing tools
• Holtzman, L. & Gersbach, C.A. "Editing the epigenome: reshaping the genomic landscape." Annual Review of Genomics and Human Genetics 19, 43-71 (2018). — Review of epigenome engineering approaches
• ClinicalTrials.gov: Tune Therapeutics HBV trial — Trial registration and status updates
• Hilton, I.B. et al. "Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers." Nature Biotechnology 33, 510-517 (2015). — Seminal paper on dCas9-p300 gene activation
• Brocken, D.J.W. et al. "dCas9: a versatile tool for epigenome editing." Current Opinion in Chemical Biology 51, 106-114 (2019). — Review of dCas9 fusion protein applications
• Vojta, A. et al. "Repurposing the CRISPR-Cas9 system for targeted DNA methylation." Nucleic Acids Research 44, 5615-5628 (2016). — Early work on dCas9-DNMT3A fusions

Last updated: October 2025.