The core promoter determines not only where gene transcription initiates but also the transcriptional activity in both basal and enhancer-induced conditions. Multiple short sequence elements within the core promoter have been identified in different species, but how they function together and to what extent they are truly species-specific has remained unclear. In this issue of Genes & Development,

Eusocial insect reproductive females show strikingly longer life spans than nonreproductive female workers despite high genetic similarity. In the ant Harpegnathos saltator (Hsal), workers can transition to reproductive “gamergates,” acquiring a fivefold prolonged life span by mechanisms that are poorly understood. We found that gamergates have elevated expression of heat shock response (HSR) genes

Translation of maternal mRNAs is detected before transcription of zygotic genes and is essential for mammalian embryo development. How certain maternal mRNAs are selected for translation instead of degradation and how this burst of translation affects zygotic genome activation remain unknown. Using gene-edited mice, we document that the oocyte-specific eukaryotic translation initiation factor 4E family

DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140)

A wide range of sequencing methods has been developed to assess nascent RNA transcription and resolve the single-nucleotide position of RNA polymerase genome-wide. These techniques are often burdened with high input material requirements and lengthy protocols. We leveraged the template-switching properties of thermostable group II intron reverse transcriptase (TGIRT) and developed Butt-seq (bulk analysis

RNA granules are mesoscale assemblies that form in the absence of limiting membranes. RNA granules contain factors for RNA biogenesis and turnover and are often assumed to represent specialized compartments for RNA biochemistry. Recent evidence suggests that RNA granules assemble by phase separation of subsoluble ribonucleoprotein (RNP) complexes that partially demix from the cytoplasm or nucleoplasm

The RNA polymerase II core promoter is the site of convergence of the signals that lead to the initiation of transcription. Here, we performed a comparative analysis of the downstream core promoter region (DPR) in Drosophila and humans by using machine learning. These studies revealed a distinct human-specific version of the DPR and led to the use of machine learning models for the identification of

The majority of our genome is composed of repeated DNA sequences that assemble into heterochromatin, a highly compacted structure that constrains their mutational potential. How heterochromatin forms during development and how its structure is maintained are not fully understood. Here, we show that mouse heterochromatin phase-separates after fertilization, during the earliest stages of mammalian embryogenesis

Cohesin is an ATPase that drives chromosome organization through the generation of intramolecular loops and sister chromatid cohesion. Cohesin's ATPase is stimulated by Scc2 binding but attenuated by acetylation of its Smc3 subunit. In this issue of Genes & Development, Boardman and colleagues (pp. 277–290) take a genetic approach to generate a mechanistic model for the opposing regulation of cohesin's

The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesin's two ATPases, formed by the Smc1p and Smc3p subunits. Cohesin's ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway—the most predominantly mutated pathway in this disease—turns MYC into not only a driver but also a facilitator of melanoma progression, with

Several rRNA-modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18S rRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a noncatalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mislocalizes DIMT1 to

Individual elements within a superenhancer can act in a cooperative or temporal manner, but the underlying mechanisms remain obscure. We recently identified an Irf8 superenhancer, within which different elements act at distinct stages of type 1 classical dendritic cell (cDC1) development. The +41-kb Irf8 enhancer is required for pre-cDC1 specification, while the +32-kb Irf8 enhancer acts to support

Congenital genetic disorders affecting limb morphology in humans and other mammals are particularly well described, due to both their rather high frequencies of occurrence and the ease of their detection when expressed as severe forms. In most cases, their molecular and cellular etiology remained unknown long after their initial description, often for several decades, and sometimes close to a century

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines

Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent ferroptosis

Since it was first described >20 yr ago, the SPOC domain (Spen paralog and ortholog C-terminal domain) has been identified in many proteins all across eukaryotic species. SPOC-containing proteins regulate gene expression on various levels ranging from transcription to RNA processing, modification, export, and stability, as well as X-chromosome inactivation. Their manifold roles in controlling transcriptional

Distinct subcellular localizations of mRNAs have been described across a wide variety of cell types. While common themes emerge for neuronal cells, functional roles of mRNA localization in space and time are much less understood in nonneuronal cells. Emerging areas of interest are cell models with protrusions, often linked with cell mobility in cancer systems. In this issue of Genes & Development,

Subcellular localization of messenger RNA (mRNA) is a widespread phenomenon that can impact the regulation and function of the encoded protein. In nonneuronal cells, specific mRNAs localize to cell protrusions, and proper mRNA localization is required for cell migration. However, the mechanisms by which mRNA localization regulates protein function in this setting remain unclear. Here, we examined the

Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found

Transfer RNAs (tRNAs) are small adaptor RNAs essential for mRNA translation. Alterations in the cellular tRNA population can directly affect mRNA decoding rates and translational efficiency during cancer development and progression. To evaluate changes in the composition of the tRNA pool, multiple sequencing approaches have been developed to overcome reverse transcription blocks caused by the stable

DNA replication is complex and highly regulated, and DNA replication errors can lead to human diseases such as cancer. DNA polymerase ε (polε) is a key player in DNA replication and contains a large subunit called POLE, which possesses both a DNA polymerase domain and a 3′–5′ exonuclease domain (EXO). Mutations at the EXO domain and other missense mutations on POLE with unknown significance have been

Zygotic genome activation has been extensively studied in a variety of systems including flies, frogs, and mammals. However, there is comparatively little known about the precise timing of gene induction during the earliest phases of embryogenesis. Here we used high-resolution in situ detection methods, along with genetic and experimental manipulations, to study the timing of zygotic activation in

Throughout the eukaryotic kingdoms, small RNAs direct chromatin modification. ARGONAUTE proteins sit at the nexus of this process, linking the small RNA information to the programming of chromatin. ARGONAUTE proteins physically incorporate the small RNAs as guides to target specific regions of the genome. In this issue of Genes & Development, Wang and colleagues (pp. 103–118) add substantial new detail

DNA double-strand break (DSB) repair is initiated by DNA end resection. CtIP acts in short-range resection to stimulate MRE11–RAD50–NBS1 (MRN) to endonucleolytically cleave 5′-terminated DNA to bypass protein blocks. CtIP also promotes the DNA2 helicase–nuclease to accelerate long-range resection downstream from MRN. Here, using AlphaFold2, we identified CtIP-F728E-Y736E as a separation-of-function

RNA-directed DNA methylation in plants is guided by 24-nt siRNAs generated in parallel with 23-nt RNAs of unknown function. We show that 23-nt RNAs function as passenger strands during 24-nt siRNA incorporation into AGO4. The 23-nt RNAs are then sliced into 11- and 12-nt fragments, with 12-nt fragments remaining associated with AGO4. Slicing recapitulated with recombinant AGO4 and synthetic RNAs reveals

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant

Pol2 is the leading-strand DNA polymerase in budding yeast. Here we describe an antagonism between its conserved POPS (Pol2 family-specific catalytic core peripheral subdomain) and exonuclease domain and the importance of this antagonism in genome replication. We show that multiple defects caused by POPS mutations, including impaired growth and DNA synthesis, genome instability, and reliance on other

Most readers of Genes & Development today may not appreciate that the birth of the journal, in 1987, was an effort for scientists to take control over editorial decisions and publishing at the highest levels. At the time, Cell, Science, and Nature each used a professional editorial staff and had not yet metastasized into innumerable specialty journals. Few nonprofit alternatives existed for submitting

Making an important scientific discovery is just the first step in a process. One also needs to communicate that scientific discovery and its impact, and get it accepted into the mainstream of research in order to advance a field. Communicating discoveries is where scientific journals play a critical role through their implementation of the peer review process and dissemination of the findings. This

While a career in research can be one of the most interesting and rewarding of endeavors, it is marked by highs and lows that are often associated with getting the fruits of our labors published. I'm sure all scientists have had the experience of crushing disappointment when the reviewers of our work fail to grasp the significance of our study or identify defects that may be real but are more often

It has taken me a long time to figure out how to start writing this piece. I want to draw attention to the words in the title, give a personal perspective, and remain scientifically focused. This is probably too ambitious, and it is unlikely that I will achieve it.

It is hard to imagine Genes & Development without Terri Grodzicker at the helm. Her steady leadership over several decades established the journal as a leading publication for molecular genetics. Like many others, we have received our fair share of reviews from G&D submissions, with a few papers sneaking into final published form. Through all of this, Terri's hand was apparent—identifying the key message

I first learned about Genes & Development when I was a postdoc in Rudolf Jaenisch's lab at the Whitehead Institute in 1987. At the time, the journal had just launched, and Rudolf suggested we submit a paper on a new retroviral insertional mouse mutant, Mov34. Fortunately, it was well reviewed and published that year (Soriano et al. 1987). It took me then a few years until I obtained enough data for

I am honored to have the opportunity to express my deepest appreciation for Dr. Terri Grodzicker's monumental role in leading the scientific journal Genes & Development through its formative years and, subsequently, through dramatic ongoing changes in molecular biology research and in the scientific publication landscape. Notably, Terri's contributions to science have extended well beyond G&D as a

Like a book, you certainly cannot judge a journal by its cover. However, you can say a lot about a journal by its Editor, and when it comes to Dr. Terri Grodzicker and her journal Genes & Development, there are many wonderful things to say. G&D has been publishing superb, groundbreaking papers in the areas of biochemistry, genetics, genomics, cellular biology, and development for many years now, providing

As Terri Grodzicker transitions from her decades-long position as Editor of Genes & Development, I salute her service to the scientific community, her integrity, and her sense of fairness that marked her career. I also proudly acknowledge our friendship that has grown steadily throughout our scientific exchanges.

I am writing this letter on the eve of Terri Grodzicker's stepping down as the long-standing Editor of Genes & Development. I wish to acknowledge and thank Terri for her many years of service to the scientific fields of development, molecular genetics, and, more broadly, molecular biology through her steady editorial guidance of this important journal. Indeed, it has always been my view that basic

I first met Terri Grodzicker almost 50 years ago. She may not remember it, as I was a new Cold Spring Harbor Laboratory graduate student from Stony Brook; in fact, the first one in a new program. I was about to begin a project in bacterial genetics in the Demerec lab, while Terri was an independent investigator working on the much sexier adenovirus in the James lab up the hill. And while my 4–5 years

It is a pleasure to contribute this short perspective to commemorate Terri Grodzicker's remarkable 35 years as Editor of Genes & Development, one of the foremost journals at the interface of gene regulation and developmental biology. The Levine lab has published 30 papers in G&D during Terri's tenure, and her generous stewardship of these papers attests to her patience, humor, and breadth of scholarship

When I started my independent research lab in 1989, I did not know Terri Grodzicker and I did not realize that she was just beginning what would become her decades-long leadership of Genes & Development. G&D had been founded just 2 years before (Inglis 2007), and as my lab developed I watched G&D rapidly join the ranks of the most respected, most influential, and most selective molecular biology journals

Dear Terri, it is a very special privilege and honor for me to write this note of thanks for your lasting and impactful contribution to the advancement of science through your 35 yr of service as the Editor of Genes & Development (which we all refer to, of course, as “G&D”). Under your leadership, G&D quickly and very impressively rose to the top tier of journals in the biological sciences, and it

Terri Grodzicker is the journal Editor that scientists dream of—brilliant and curious, fair and unbiased, highly critical, broadly and deeply knowledgeable, and not distracted by fads or hype. She is able to keep her professional distance while supporting hopeful authors, many of whom have become her lifelong friends. Terri was already a highly accomplished scientist when she became the Editor who

One of the hidden pleasures of life as a scientist is the connections to colleagues who become friends and who remain both colleagues and friends over decades. Terri Grodzicker is one of those people who seem to do this effortlessly and enthusiastically, serving as the hub of an amazing group of scientists whom she has met and befriended, and collecting those who have helped keep Genes & Development

There is no lack of tweeting and editorial opinion claiming that scientific publishing—and above all, publishing house-managed peer review—is dead, or at least fatally flawed. Some go so far as to declare that scientific publishing antagonizes scientists: It works against the scientific process and constrains careers because the industry is a machine run by money-grabbing entrepreneurs. I admit that

Over my career, now spanning some four decades, I've published 22 papers in Genes & Development. Terri Grodzicker has been the Editor for all of these. From my lab's first experience with G&D in 1989 to our most recent in 2022, Terri has always been both expeditious in handling our review process and thoughtful and fair in her judgment and decisions. In the publishing world, Terri stands out as someone

Finally, I can sit in the catbird seat and pass judgement on the Editor!

I am delighted to participate in this celebration of Terri Grodzicker and her role as the Editor of Genes & Development. Soon after I began publishing in G&D, I came to admire her as a skilled Editor and a keen observer of the human condition. Beyond her role as Editor of G&D, Terri played many other important roles at Cold Spring Harbor Laboratory: as a lab head, as an organizer of the many meetings

In 1989, when I learned that Terri Grodzicker was going to be Editor of Genes & Development, some primitive part of my brain breathed a sigh of relief: “At last, someone I know who can grease the path to publication of my manuscripts!” How wrong I was.

It is difficult to imagine Genes & Development without Terri Grodzicker and vice versa. Terri embodied G&D. During Terri's reign, G&D became a steadfast, reliable journal that knows what it is (and what it is not). It stands for high-quality, high-interest, serious science. Terri avoided gimmicks and was not swayed by fashions. She was not tempted to start an extended family of G&D-adjacent journals

It is an immense pleasure to write about Dr. Terri Grodzicker as a tremendous advocate for cutting-edge research and for scientific interactions, and how she expanded her influence following a distinguished research career. My view is that Terri has been a leader worldwide to promote scientific discourse in her second career combining her roles as Editor of Genes & Development and leading Cold Spring

Even before Genes & Development, Terri Grodzicker and I had developed a special relationship—we were both smokers. When I was promoted to the Cold Spring Harbor Laboratory staff in 1984, I inherited the departing Steve Hughes’ desk in the office he had shared with Terri. As such, during office gossiping sessions, our office would fill with a thick haze of smoke. Its seriousness was vividly brought

Terri and I met at Cold Spring Harbor Laboratory nearly half a century ago as junior scientists in the James lab. Both of us were studying adenovirus. Our work was complementary and we wrote three papers together, dealing with viral genes that encoded regulatory proteins and RNAs. The last of these papers, coauthored with Elizabeth Moran, Rich Roberts, and Brad Zerler, was on gene expression and cellular

It is difficult to imagine the scientific publishing landscape without Terri Grodzicker at the helm of Genes & Development. Here we celebrate over 50 years of Terri's many accomplishments and awesome staying power, first as a bench scientist with a stellar decades-long career in molecular genetics in Boston and Cold Spring Harbor, and then as Editor of G&D since 1989—where did the time go?

I have known Terri Grodzicker for over four decades as a colleague and friend. So it is a distinct and personal pleasure to write this deep appreciation of Terri's stewardship of Genes & Development. Terri took over the journal in the late 1980s, after having established a flourishing career as an independent scientist for many years at Cold Spring Harbor Laboratory, one of the premier institutions

The rapid advances in the research of gene regulation and development in the 1980s, sparked by the cloning of key regulatory genes and functional analysis of cell type-specific gene expression, set the ground for establishing new journals for publishing. Discussions between the late Steve Prentis, Director of Publications at Cold Spring Harbor Laboratory, and Richard Flavell, then Senior Secretary

This January 2023 special issue of Genes & Development is an appreciation of the work of the journal's Editor, Terri Grodzicker, who stepped down in December 2022 after 35 years of distinguished service. It consists of personal essays specially commissioned from 28 prominent scientists, to whom we are grateful for accepting the invitation and bringing such care and thoughtfulness to the task. They

The editors would like to thank the Editorial Board and the following scientists who reviewed papers and provided advice during 2022.

Transcription factors are defined by their sequence-specific binding to DNA and by their selective impacts on gene expression, depending on specific binding sites. The factor binding motifs in the DNA should thus represent a blueprint of regulatory logic, suggesting that transcription factor binding patterns on the genome (e.g., measured by ChIP-seq) should indicate which target genes the factors are

In most eukaryotes, constitutive heterochromatin, defined by histone H3 lysine 9 methylation (H3K9me), is enriched on repetitive DNA, such as pericentromeric repeats and transposons. Furthermore, repetitive transgenes also induce heterochromatin formation in diverse model organisms. However, the mechanisms that promote heterochromatin formation at repetitive DNA elements are still not clear. Here,