TAL1/SCL is a hematopoietic-specific oncogene and its activity is regulated by 
associated transcriptional co-activators and corepressors. Dysregulation of TAL1 
activity has been associated with T-cell leukemogenesis. However, it remains 
unclear how the interactions between TAL1 and corepressors versus co-activators 
are properly regulated. Here, we reported that protein kinase A (PKA)-mediated 
phosphorylation regulates TAL1 interaction with the lysine-specific demethylase 
(LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. 
Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 
interaction leading to promoter H3K4 hypermethylation and activation of target 
genes that have been suppressed in normal and malignant hematopoiesis. Knockdown 
of TAL1 or LSD1 led to a derepression of the TAL1 target genes in T-cell acute 
lymphoblast leukemia (T-ALL) Jurkat cells, which is accompanied by elevating 
promoter H3K4 methylation. Similarly, treatment of PKA activator forskolin 
resulted in derepression of target genes by reducing its interaction with LSD1 
while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels. 
Consistent with the dual roles of TAL1 in transcription, TAL1-associated LSD1 is 
decreased while recruitment of hSET1 is increased at the TAL1 targets during 
erythroid differentiation. This process is accompanied by a dramatic increase in 
H3K4 methylation. Thus, our data revealed a novel interplay between PKA 
phosphorylation and TAL1-mediated epigenetic regulation that regulates 
hematopoietic transcription and differentiation programs during hematopoiesis 
and leukemogenesis.