Biomedical subjects

Lingyun Long

Publications and source records attributed to Lingyun Long.

3 recordsLinked to original sources

PubMed2025

KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.

UNLABELLED: NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia. SIGNIFICANCE: KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.

Humans↗

PubMed2004

Striking differences between the mouse and the human alpha-fetoprotein enhancers.

The alpha-fetoprotein (AFP) gene is expressed abundantly in the fetal liver and transcriptionally repressed in the adult liver, but can be reactivated during liver regeneration and in liver tumors. Previous studies identified three enhancers, E1, E2, and E3, upstream of the mouse and rat Afp genes and a single enhancer upstream of the human gene. We have compared the sequences upstream of the rodent and primate AFP genes. Our analysis demonstrates that the previously identified human enhancer is the counterpart to mouse E2. This comparison also reveals that a functional primate counterpart to the rodent E1 is absent due to a deletion that removes the core region of this enhancer. Furthermore, our studies identify a novel human enhancer corresponding to rodent E3. Despite the overall similarity of E3 between human and mouse, we found differences in transcription factor binding sites between these species. A C/EBP binding site is conserved but two other motifs in rodent E3, one that binds orphan nuclear receptors and a second that binds FoxA proteins, are not conserved in humans. The human counterpart to the rodent FoxA site can bind COUP-TF factors. Despite the overall sequence similarity in E3 between mice and humans, the difference in factor binding sites in E3, as well as the absence of E1 in primates, indicates that different mechanisms regulate AFP transcription in these different species.

Animals↗

PubMed2004

FoxA proteins regulate H19 endoderm enhancer E1 and exhibit developmental changes in enhancer binding in vivo.

Multiple enhancers govern developmental and tissue-specific expression of the H19-Igf2 locus, but factors that bind these elements have not been identified. Using chromatin immunoprecipitation, we have found two FoxA binding sites in the H19 E1 enhancer. Mutating these sites diminishes E1 activity in hepatoma cells. Additional chromatin immunoprecipitations show that FoxA binds to E1 in fetal liver, where H19 is abundantly expressed, but that binding decreases in adult liver, where H19 is no longer transcribed, even though FoxA proteins are present at both times. FoxA proteins are induced when F9 embryonal carcinoma cells differentiate into visceral endoderm (VE) and parietal endoderm (PE). We show that FoxA binds E1 in VE cells, where H19 is expressed, but not in PE cells, where H19 is silent. This correlation between FoxA binding and H19 expression indicates a role for FoxA in regulating H19, including developmental activation in the yolk sac and liver and postnatal repression in the liver. This is the first demonstration of a tissue-specific factor involved in developmental control of H19 expression. These data also indicate that the presence of FoxA proteins is not sufficient for binding but that additional mechanisms must govern the accessibility of FoxA proteins to their cognate binding sites within the H19 E1 enhancer.

Acetylation↗