Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

Development of Plasmodium-specific liver-resident memory CD8+ T cells after heat-killed sporozoite immunization in mice.

Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation-attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8+ memory T cells, with liver-resident memory T cells (TRM ) being particularly important. We have previously described a TCR transgenic mouse, termed PbT-I, where all CD8+ T cells recognize a specific peptide from Plasmodium. PbT-I form liver TRM cells upon RAS injection and are capable of protecting mice against challenge infection. Here, we utilize this transgenic system to examine whether nonliving sporozoites, killed by heat treatment (HKS), could trigger the development of Plasmodium-specific liver TRM cells. We found that HKS vaccination induced the formation of memory CD8+ T cells in the spleen and liver, and importantly, liver TRM cells were fewer in number than that induced by RAS. Crucially, we showed the number of TRM cells was significantly higher when HKS were combined with the glycolipid α-galactosylceramide as an adjuvant. In the future, this work could lead to development of an antimalaria vaccination strategy that does not require live sporozoites, providing greater utility.

MOZ directs the distal-less homeobox gene expression program during craniofacial development.

Oral clefts are common birth defects. Individuals with oral clefts who have identical genetic mutations regularly present with variable penetrance and severity. Epigenetic or chromatin-mediated mechanisms are commonly invoked to explain variable penetrance. However, specific examples of these are rare. Two functional copies of the MOZ (KAT6A, MYST3) gene, encoding a MYST family lysine acetyltransferase chromatin regulator, are essential for human craniofacial development, but the molecular role of MOZ in this context is unclear. Using genetic interaction and genomic studies, we have investigated the effects of loss of MOZ on the gene expression program during mouse development. Among the more than 500 genes differentially expressed after loss of MOZ, 19 genes had previously been associated with cleft palates. These included four distal-less homeobox (DLX) transcription factor-encoding genes, Dlx1, Dlx2, Dlx3 and Dlx5 and DLX target genes (including Barx1, Gbx2, Osr2 and Sim2). MOZ occupied the Dlx5 locus and was required for normal levels of histone H3 lysine 9 acetylation. MOZ affected Dlx gene expression cell-autonomously within neural crest cells. Our study identifies a specific program by which the chromatin modifier MOZ regulates craniofacial development.

Monitoring Behaviors of Patients With Late-Stage Dementia Using Passive Environmental Sensing Approaches: A Case Series.

OBJECTIVE: To show the feasibility of using different unobtrusive activity-sensing technologies to provide objective behavioral markers of persons with dementia (PwD). DESIGN: Monitored the behaviors of two PwD living in memory care unit using the Oregon Center for Aging & Technology (ORCATECH) platform, and the behaviors of two PwD living in assisted living facility using the Emerald device. SETTING: A memory care unit in Portland, Oregon and an assisted living facility in Framingham, Massachusetts. PARTICIPANTS: A 63-year-old male with Alzheimer's disease (AD), and an 80-year-old female with frontotemporal dementia, both lived in a memory care unit in Portland, Oregon. An 89-year-old woman with a diagnosis of AD, and an 85-year-old woman with a diagnosis of major neurocognitive disorder, Alzheimer's type with behavioral symptoms, both resided at an assisted living facility in Framingham, Massachusetts. MEASUREMENTS: These include: sleep quality measured by the bed pressure mat; number of transitions between spaces and dwell times in different spaces measured by the motion sensors; activity levels measured by the wearable actigraphy device; and couch usage and limb movements measured by the Emerald device. RESULTS: Number of transitions between spaces can identify the patient's episodes of agitation; activity levels correlate well with the patient's excessive level of agitation and lack of movement when the patient received potentially inappropriate medication and neared the end of life; couch usage can detect the patient's increased level of apathy; and periodic limb movements can help detect risperidone-induced side effects. This is the first demonstration that the ORCATECH platform and the Emerald device can measure such activities. CONCLUSION: The use of technologies for monitoring behaviors of PwD can provide more objective and intensive measurements of PwD behaviors.

PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia.

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.

Disaggregating Data to Measure Racial Disparities in COVID-19 Outcomes and Guide Community Response - Hawaii, March 1, 2020-February 28, 2021.

Native Hawaiian and Pacific Islander populations have been disproportionately affected by COVID-19 (1-3). Native Hawaiian, Pacific Islander, and Asian populations vary in language; cultural practices; and social, economic, and environmental experiences,† which can affect health outcomes (4).§ However, data from these populations are often aggregated in analyses. Although data aggregation is often used as an approach to increase sample size and statistical power when analyzing data from smaller population groups, it can limit the understanding of disparities among diverse Native Hawaiian, Pacific Islander, and Asian subpopulations¶ (4-7). To assess disparities in COVID-19 outcomes among Native Hawaiian, Pacific Islander, and Asian populations, a disaggregated, descriptive analysis, informed by recommendations from these communities,** was performed using race data from 21,005 COVID-19 cases and 449 COVID-19-associated deaths reported to the Hawaii State Department of Health (HDOH) during March 1, 2020-February 28, 2021.†† In Hawaii, COVID-19 incidence and mortality rates per 100,000 population were 1,477 and 32, respectively during this period. In analyses with race categories that were not mutually exclusive, including persons of one race alone or in combination with one or more races, Pacific Islander persons, who account for 5% of Hawaii's population, represented 22% of COVID-19 cases and deaths (COVID-19 incidence of 7,070 and mortality rate of 150). Native Hawaiian persons experienced an incidence of 1,181 and a mortality rate of 15. Among subcategories of Asian populations, the highest incidences were experienced by Filipino persons (1,247) and Vietnamese persons (1,200). Disaggregating Native Hawaiian, Pacific Islander, and Asian race data can aid in identifying racial disparities among specific subpopulations and highlights the importance of partnering with communities to develop culturally responsive outreach teams§§ and tailored public health interventions and vaccination campaigns to more effectively address health disparities.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Radio Signal Sensing and Signal Processing to Monitor Behavioral Symptoms in Dementia: A Case Study.

OBJECTIVES: Alzheimer's Disease (AD)-related behavioral symptoms (i.e. agitation and/or pacing) develop in nearly 90% of AD patients. In this N = 1 study, we provide proof-of-concept of detecting changes in movement patterns that may reflect underlying behavioral symptoms using a highly novel radio sensor and identifying environmental triggers. METHODS: The Emerald device is a Wi-Fi-like box without on-body sensors, which emits and processes radio-waves to infer patient movement, spatial location and activity. It was installed for 70 days in the room of patient 'E', exhibiting agitated behaviors. RESULTS: Daily motion episode aggregation revealed motor activity fluctuation throughout the data collection period which was associated with potential socio-environmental triggers. We did not detect any adverse events attributable to the use of the device. CONCLUSION: This N-of-1 study suggests the Emerald device is feasible to use and can potentially yield actionable data regarding behavioral symptom management. No active or potential device risks were encountered.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

HPV vaccination prevalence, parental barriers and motivators to vaccinating children in Hawai'i.

Objective: To determine the prevalence and barriers to human papillomavirus (HPV) vaccine uptake among 11-18 year olds in the Hawai'i's four major ethnic groups-Native Hawaiians, Filipinos, Japanese, and Caucasians. Study design: A telephone survey assessed parents' knowledge of HPV and the HPV vaccine, status of their child's HPV vaccine uptake, variables operationalizing the Health Belief Model, and barriers and motivators to uptake. Results: Across the groups, 799 parents completed the survey. About 35% of daughters and 19% of sons had received all three shots. Although ethnic differences in vaccine uptake were seen in bivariate analysis (with significantly lower uptake in Filipino youth), in multivariable logistic regression analysis, only Caucasian parents were significantly less likely to start their sons on the HPV vaccine series compared with Japanese parents (reference group). Having heard about the vaccine, believing in its effectiveness, and older age of the child were also associated with vaccine uptake. Motivators for HPV vaccination were physician's recommendation and wanting to protect one's child. The primary barrier to uptake was lack of knowledge about the vaccine. Conclusions: Findings reinforce the fact that a physician's recommendation and receipt of information about the vaccine are strong motivators for parents to vaccinate their children, regardless of ethnicity.

Divergence between genes but limited allelic polymorphism in two MHC class II A genes in Leach's storm-petrels Oceanodroma leucorhoa.

The major histocompatibility complex (MHC) is critical to host-pathogen interactions. Class II MHC is a heterodimer, with α and ß subunits encoded by different genes. The peptide-binding groove is formed by the first domain of both subunits (α1 and ß1), but studies of class II variation or natural selection focus primarily on the ß subunit and II B genes. We explored MHC II A in Leach's storm-petrel, a seabird with two expressed, polymorphic II B genes. We found two II A genes, Ocle-DAA and Ocle-DBA, in contrast to the single II A gene in chicken and duck. In exon 2 which encodes the α1 domain, the storm-petrel II A genes differed strongly from each other but showed little within-gene polymorphism in 30 individuals: just one Ocle-DAA allele, and three Ocle-DBA alleles differing from each other by single non-synonymous substitutions. In a comparable sample, the two II B genes had nine markedly diverged alleles each. Differences between the α1 domains of Ocle-DAA and Ocle-DBA showed signatures of positive selection, but mainly at non-peptide-binding site (PBS) positions. In contrast, positive selection within and between the II B genes corresponded to putative PBS codons. Phylogenetic analysis of the conserved α2 domain did not reveal deep or well-supported lineages of II A genes in birds, in contrast to the pronounced differentiation of DQA, DPA, and DRA isotypes in mammals. This uncertain homology complicates efforts to compare levels of functional variation and modes of evolution of II A genes across taxa.

Classification of intra-specific variation in plant functional strategies reveals adaptation to climate.

Background and Aims: In plants, extensive intra-specific variation exists in the allocation of resources between vegetative growth and reproduction, reflecting different functional strategies. A simple method for the classification of intra-specific variation in these strategies would enable characterization of evolutionary and ecological processes. Methods: C-S-R theory can be applied to classify functional strategies (competitive C; stress tolerant, S; ruderal, R) in different plant species. Using a diverse set of arabidopsis ( Arabidopsis thaliana ) accessions grown under common conditions, it was tested whether a simple approach designed for allocating C-S-R strategies at the species level can also be used to analyse intra-specific variation. Key Results: Substantial intra-specific variation between arabidopsis accessions was found along the S-R axis. There was a positive correlation of temperature at the geographical origin with the dimension of S and a negative correlation with the dimension of R. Flowering time in a natural annual cycle and leaf dry matter content were identified as the main determinants of this adaptation, with plants originating from warmer climates having a higher leaf dry matter content and flowering earlier in a common garden. Conclusions: It was shown that functional strategies reflect adaptation to climate, with consequences for important traits such as fecundity and total plant dry weight. The approach could be used in genome-wide association studies to determine the genetic basis of functional strategies in wild species or crops.

Improving Human Papillomavirus (HPV) Vaccination in the Postpartum Setting.

Although the HPV vaccine has been shown to be highly effective in preventing cervical dysplasia, vaccination rates remain low. The objective of this study was to assess the effectiveness of an electronic medical record (EMR) prompt on HPV vaccination rates in the postpartum setting. We conducted a pre-post intervention study among postpartum women ages 18-26 seen at an outpatient clinic from 09/01/2012-08/31/2013 (pre-intervention) and from 10/01/2013-03/31/2014 (post-intervention). The intervention was a drop-down menu that was inserted into the EMR postpartum note template inquiring about the patient's HPV vaccination status and whether or not the vaccine was administered at that visit. HPV vaccination uptake was compared pre and post-intervention. Of the 278 postpartum visits during the study period, 241 were eligible for analysis. There was a significant increase of the HPV vaccine uptake, from 1.2 % (2/173) among pre-intervention visits to 26.5 % (18/68) among post-intervention visits (p < 0.001). After adjusting for age, ethnicity, insurance, and religion, HPV vaccination was significantly higher at postpartum visits during the intervention period, with an adjusted OR = 93.49 [95 % CI 15.29-571.52]. Among visits in which the vaccine was not given, HPV vaccination was not discussed in 46 % and patients refused the vaccine in 40 % of visits. An EMR prompt in the postpartum note could be an effective way to promote HPV vaccination in the postpartum setting. It will likely take a combination of strategies to optimize vaccination uptake.

Human Papillomavirus (HPV) Vaccination Motivators, Barriers, and Brochure Preferences Among Parents in Multicultural Hawai'i: a Qualitative Study.

The human papillomavirus (HPV) vaccine can prevent cervical and other cancers. Unfortunately, according to the National Immunization Survey-Teen 2014 data, completion of the HPV vaccine was only 38 % for 13- to 17-year-old girls and 31 % for 13- to17-year-old boys in the USA, and prevalence was similar in Hawai'i. Parents' acceptability of the HPV vaccine is critical for the vaccine uptake, and this can be increased by educational materials and interventions. However, HPV materials are not widely distributed in Hawai'i. The purpose of this qualitative study was to identify HPV vaccination barriers, motivators, and brochure preferences among parents of teens in multicultural Hawai'i. Twenty parents were interviewed in person or by telephone. Four major themes emerged: (1) the physician is critical in the decision to vaccinate, (2) parental perception of the child's sexual activity guides the timing of their willingness to vaccinate, (3) HPV health education materials should be provided and discussed by the physician, and (4) parents would prefer an educational brochure that features local faces and testimonials, includes an immunization chart, and addresses barriers to vaccination. These findings informed the development of HPV health education materials tailored to Asian Americans and Pacific Islanders in Hawai'i.

Promoting and Providing HPV Vaccination in Hawaii: Barriers Faced by Health Providers.

Despite the availability of HPV prophylactic vaccines, uptake has been suboptimal in the US. In the state of Hawaii, HPV vaccine coverage has decreased among females and remains low among males aged 13-17. The reasons for low uptake are unknown and may indicate the existence of critical barriers to HPV vaccination. The purpose of this investigation was to identify policy, system and environmental barriers and promoters of pediatric HPV vaccination in Hawaii. An online 86-item survey addressing knowledge, attitudes, beliefs, practices, and barriers to HPV vaccination was distributed to practicing physicians in Hawaii specializing in Pediatrics, Family Medicine, and Obstetrics-Gynecology. Survey responses were received from a total of 120 physicians. Private practice physicians reported more concerns with vaccine ordering and stocking costs (p < 0.0001), reimbursement levels (p < 0.0001), and insurance coverage (p < 0.0001) compared to physicians in large group practices. Eighty-three percent of providers cited lack of parent knowledge and understanding of HPV infection as a barrier. Over half of physicians (58 %) reported that completion of the 3-dose schedule was a barrier. Most physicians did not use tracking or reminder systems to ensure dose completion. A majority (58 %) of providers cited the lack of school-based vaccination requirements as a barrier. Uptake of HPV vaccination in Hawaii may be impeded by physician perception of parent knowledge and attitudes. Cost-related system barriers are particular barriers among those in private practice. Completion of the 3-dose schedule also remains a challenge.

Understanding Factors Affecting Health Providers' Perceptions of Pharmacist Roles in HPV Vaccine Administration.

Human papillomavirus (HPV) is a viral infection that sexually active females and males may be exposed to in their lifetime. The HPV vaccine is highly recommended especially among children to protect them before their anticipated exposure to HPV, however, vaccination uptake in Hawai'i remains low. As of 2017, legislation allows pharmacists to vaccinate for adolescent vaccines with the potential to increase access and opportunities for patients to complete the HPV vaccine series. Physicians in Hawai'i were surveyed to examine physicians' awareness of this law, their perceptions of the role of pharmacists, and willingness to send adolescent patients to pharmacies; 137 responses were received and analyzed. Overall, 72% (n=99) of respondents were willing while 28% (n=38) were unwilling to send patients to pharmacies for vaccines. Physicians view pharmacists' role as helpful but have concerns regarding correct administration and tracking doses given. Results show potential for more physician-pharmacist collaborations through further education and trainings for pharmacists and health providers to increase physician referrals for adolescent vaccine services in pharmacies.

Health literacy, health communication challenges, and cancer screening among rural native Hawaiian and Filipino women.

Native Hawaiians and Filipinos are disproportionately impacted by cancer and are less likely to participate in cancer screening than whites. Limited information exists about health information pathways and health communication challenges as they relate to cancer screening in these groups. Six focus groups (n=77) of Native Hawaiian and Filipino women age 40+years were conducted to investigate these research gaps. Participants noted many health information challenges. Challenges were both practical and interpersonal and included both written and oral health communication. Practical challenges included "big" words, complexity of terms, and lack of plain English. Interpersonal issues included doctors rushing, doctors not assessing comprehension, and doctors treating respondents as patients not people. Women noted that they would often not ask questions even when they knew they did not understand because they did not want the provider to think negatively of them. Overarching themes to improve cancer communication gaps included: (1) the importance of family and community in health information dissemination, (2) the key role women play in interpreting health information for others, (3) the importance of personal experience and relationships to the salience of health information, and (4) the desire for local cultural relevance in health communication. Findings are discussed in light of the 2010 National Action Plan for Health Literacy.

Stem cell plasticity, acetylation of H3K14, and de novo gene activation rely on KAT7.

In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.

Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest.

Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.

Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death.

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.